Forms and compositions of an erk inhibitor

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of one or both of ERK1 and ERK2.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. provisional applicationNo. 62/037,066, filed Aug. 13, 2014, the entirety of which is herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention provides various forms and compositions useful asinhibitors of ERK kinases, for example one or both of ERK1 and ERK2kinases.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases are thought tohave evolved from a common ancestral gene due to the conservation oftheir structure and catalytic function. Almost all kinases contain asimilar 250-300 amino acid catalytic domain. The kinases may becategorized into families by the substrates they phosphorylate (e.g.,protein-tyrosine, protein-serine/threonine, lipids, etc.).

The processes involved in tumor growth, progression, and metastasis aremediated by signaling pathways that are activated in cancer cells. TheMAPK or Raf-Mek-ERK pathway plays a central role in regulating mammaliancell growth by relaying extracellular signals from ligand-bound cellsurface tyrosine kinase receptors such as erbB family, PDGF, FGF, andVEGF receptor tyrosine kinase. Activation of the ERK occurs via acascade of phosphorylation events that begins with activation of Ras.Activation of Ras leads to the recruitment and activation of Raf, aserine-threonine kinase. Activated Raf then phosphorylates and activatesMEK1/2, which then phosphorylates and activates one or both of ERK1 andERK2. When activated, one or both of ERK1 and ERK2 phosphorylatesseveral downstream targets involved in a multitude of cellular eventsincluding cytoskeletal changes and transcriptional activation. TheERK/MAPK pathway is one of the most important for cell proliferation,and human tumor data suggest that the ERK/MAPK pathway is frequentlyactivated in many tumors. Ras genes, which are upstream of one or bothof ERK1 and ERK2, are mutated in several cancers including colorectal,melanoma, breast, lung, and pancreatic tumors. High Ras activity isaccompanied by elevated ERK activity in many human tumors. In addition,activating mutations of BRAF, a serine-threonine kinase of the Raffamily, are associated with increased RAF, MEK, and ERK kinase activity.Tumors types with the most frequent mutations in BRAF include melanomas(60%), thyroid cancers (greater than 40%) and colorectal cancers.

Many diseases are associated with abnormal cellular responses,proliferation and evasion of programmed cell-death, triggered by proteinkinase-mediated events as described above. Accordingly, there remains aneed to find protein kinase inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that novel forms of the present invention, andcompositions thereof, are useful as inhibitors of one or more proteinkinases and exhibit desirable characteristics for the same. In general,salt forms or freebase forms, and pharmaceutically acceptablecompositions thereof, are useful for treating or lessening the severityof a variety of diseases or disorders as described in detail herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an XRPD pattern of Form A of compound 1.

FIG. 2 depicts a DSC thermogram and TGA trace of Form A of compound 1.

FIG. 3 depicts a DVS plot of Form A of compound 1.

FIG. 4 depicts an XRPD pattern of Form B of compound 1.

FIG. 5 depicts a DSC thermogram of Form B of compound 1.

FIG. 6 depicts a TGA trace of Form B of compound 1.

FIG. 7 depicts an XRPD pattern of Form C of compound 1.

FIG. 8 depicts a DSC thermogram of Form C of compound 1.

FIG. 9 depicts a TGA trace of Form C of compound 1.

FIG. 10 depicts an XRPD pattern of Form D of compound 1.

FIG. 11 depicts a DSC thermogram of Form D of compound 1.

FIG. 12 depicts a TGA trace of Form D of compound 1.

FIG. 13 depicts an XRPD pattern of Form A of compound 2.

FIG. 14 depicts a DSC thermogram of Form A of compound 2.

FIG. 15 depicts a TGA trace of Form A of compound 2.

FIG. 16 depicts a DVS plot of Form A of compound 2.

FIG. 17 depicts an XRPD pattern of Form B of compound 2.

FIG. 18 depicts a DSC thermogram of Form B of compound 2.

FIG. 19 depicts a TGA trace of Form B of compound 2.

FIG. 20 depicts a DVS plot of Form B of compound 2.

FIG. 21 depicts an XRPD pattern of Form C of compound 2.

FIG. 22 depicts a DSC thermogram of Form C of compound 2.

FIG. 23 depicts a TGA trace of Form C of compound 2.

FIG. 24 depicts a DVS plot of Form C of compound 2.

FIG. 25 depicts an XRPD pattern of Form D of compound 2.

FIG. 26 depicts a DSC thermogram of Form D of compound 2.

FIG. 27 depicts a TGA trace of Form D of compound 2.

FIG. 28 depicts an XRPD pattern of Form A of compound 3.

FIG. 29 depicts a DSC thermogram of Form A of compound 3.

FIG. 30 depicts a TGA trace of Form A of compound 3.

FIG. 31 depicts a DVS plot of Form A of compound 3.

FIG. 32 depicts an XRPD pattern of Form A of compound 4.

FIG. 33 depicts a DSC thermogram of Form A of compound 4.

FIG. 34 depicts a TGA trace of Form A of compound 4.

FIG. 35 depicts a DVS plot of Form A of compound 4.

FIG. 36 depicts an XRPD pattern of Form B of compound 4.

FIG. 37 depicts a DSC thermogram and TGA trace of Form B of compound 4.

FIG. 38 depicts an XRPD pattern of Form C of compound 4.

FIG. 39 depicts a DSC thermogram of Form C of compound 4.

FIG. 40 depicts an XRPD pattern of Form D of compound 4.

FIG. 41 depicts a DSC thermogram of Form D of compound 4.

FIG. 42 depicts a DSC thermogram and TGA trace of Form D of compound 4.

FIG. 43 depicts a DVS plot of Form D of compound 4.

FIG. 44 depicts an XRPD pattern of Form E of compound 4.

FIG. 45 depicts a DSC thermogram of Form E of compound 4.

FIG. 46 depicts an XRPD pattern of Form F of compound 4.

FIG. 47 depicts a DSC thermogram of Form F of compound 4.

FIG. 48 depicts an XRPD pattern of Form G of compound 4.

FIG. 49 depicts a DSC thermogram of Form G of compound 4.

FIG. 50 depicts an XRPD pattern of Form H of compound 4.

FIG. 51 depicts a DSC thermogram of Form H of compound 4.

FIG. 52 depicts an XRPD pattern of Form I of compound 4.

FIG. 53 depicts an XRPD pattern of Form A of compound 5.

FIG. 54 depicts a DSC thermogram of Form A of compound 5.

FIG. 55 depicts a TGA trace of Form A of compound 5.

FIG. 56 depicts a DVS plot of Form A of compound 5.

FIG. 57 depicts an XRPD pattern of Form B of compound 5.

FIG. 58 depicts a DSC thermogram and TGA trace of Form B of compound 5.

FIG. 59 depicts an XRPD pattern of Form C of compound 5.

FIG. 60 depicts a DSC thermogram and TGA trace of Form C of compound 5.

FIG. 61 depicts an XRPD pattern of Form D of compound 5.

FIG. 62 depicts a DSC thermogram and TGA trace of Form D of compound 5.

FIG. 63 depicts an XRPD pattern of Form E of compound 5.

FIG. 64 depicts a DSC thermogram of Form E of compound 5.

FIG. 65 depicts a DVS plot of Form E of compound 5.

FIG. 66 depicts an XRPD pattern of Form A of compound 6.

FIG. 67 depicts a DSC thermogram of Form A of compound 6.

FIG. 68 depicts a TGA trace of Form A of compound 6.

FIG. 69 depicts a DVS plot of Form A of compound 6.

FIG. 70 depicts an XRPD pattern of Form B of compound 6.

FIG. 71 depicts a DSC thermogram and TGA trace of Form B of compound 6.

FIG. 72 depicts an XRPD pattern of Form C of compound 6.

FIG. 73 depicts a DSC thermogram and TGA trace of Form C of compound 6.

FIG. 74 depicts an XRPD pattern of Form A of compound 7.

FIG. 75 depicts a DSC thermogram and TGA trace of Form A of compound 7.

FIG. 76 depicts a DVS plot of Form A of compound 7.

FIG. 77 depicts an XRPD pattern of Form A of compound 8.

FIG. 78 depicts a DSC thermogram and TGA trace of Form A of compound 8.

FIG. 79 depicts an XRPD pattern of Form B of compound 8.

FIG. 80 depicts a DSC thermogram and TGA trace of Form B of compound 8.

FIG. 81 depicts an XRPD pattern of Form C of compound 8.

FIG. 82 depicts a DSC thermogram and TGA trace of Form C of compound 8.

FIG. 83 depicts a DVS plot of Form C of compound 8.

FIG. 84 depicts a DSC thermogram and TGA trace of Form D of compound 8.

FIG. 85 depicts an XRPD pattern of Form A of compound 9.

FIG. 86 depicts a DSC thermogram and TGA trace of Form A of compound 9.

FIG. 87 depicts a DVS plot of Form A of compound 9.

FIG. 88 depicts a DSC thermogram and TGA trace of Form B of compound 9.

FIG. 89 depicts a DSC thermogram and TGA trace of Form A of compound 10.

FIG. 90 depicts an XRPD pattern of Form B of compound 10.

FIG. 91 depicts a DSC thermogram and TGA trace of Form B of compound 10.

FIG. 92 depicts an XRPD pattern of Form A of compound 11.

FIG. 93 depicts a DSC thermogram and TGA trace of Form A of compound 11.

FIG. 94 depicts an XRPD pattern of Form A of compound 12.

FIG. 95 depicts a DSC thermogram and TGA trace of Form A of compound 12.

FIG. 96 depicts an XRPD pattern of Form B of compound 12.

FIG. 97 depicts a DSC thermogram and TGA trace of Form B of compound 12.

FIG. 98 depicts an XRPD pattern of Form C of compound 12.

FIG. 99 depicts a DSC thermogram and TGA trace of Form C of compound 12.

FIG. 100A depicts PK data in dogs under fasted conditions.

FIG. 100B depicts PK data in dogs under fed conditions.

DETAILED DESCRIPTION OF THE INVENTION General Description of CertainAspects of the Invention

PCT patent application serial number PCT/US14/15256, filed Feb. 7, 2014and published as WO 2014/124230 on Aug. 14, 2014 (“the '230publication,” the entirety of which is hereby incorporated herein byreference), describes certain ERK inhibitor compounds which covalentlyand irreversibly inhibit activity of one or both of ERK1 and ERK2kinases. Such compounds include compound 1:

Compound 1,N-(2-(2-((2-methoxy-5-methylpyridin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-methylphenyl)acrylamide,is designated as compound number 1-90 in the '230 publication and thesynthesis of compound 1 is described in detail at Example 94 of the '230publication, and is reproduced herein for ease of reference.

Compound 1 is active in a variety of assays and therapeutic modelsdemonstrating covalent, irreversible inhibition of one or both of ERK1and ERK2 kinases (see, e.g., Table A of the '230 publication).Accordingly, compound 1 is useful for treating one or more disordersassociated with activity of one or both of ERK1 and ERK2.

It would be desirable to provide a solid form of compound 1 (e.g., as afreebase thereof or salt thereof) that imparts characteristics such asimproved aqueous solubility, stability and ease of formulation.Accordingly, the present invention provides both free base forms andsalt forms of compound 1.

Free Base Forms of Compound 1

It is contemplated that compound 1 can exist in a variety of physicalforms. For example, compound 1 can be in solution, suspension, or insolid form. In certain embodiments, compound 1 is in solid form. Whencompound 1 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides a form of compound 1substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude different forms of compound 1, residual solvents, or any otherimpurities that may result from the preparation of, and/or isolation of,compound 1. In certain embodiments, at least about 95% by weight of aform of compound 1 is present. In still other embodiments of theinvention, at least about 99% by weight of a form of compound 1 ispresent.

According to one embodiment, a form of compound 1 is present in anamount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weightpercent where the percentages are based on the total weight of thecomposition. According to another embodiment, a form of compound 1contains no more than about 3.0 area percent HPLC of total organicimpurities and, in certain embodiments, no more than about 1.5 areapercent HPLC total organic impurities relative to the total area of theHPLC chromatogram. In other embodiments, a form of compound 1 containsno more than about 1.0% area percent HPLC of any single impurity; nomore than about 0.6 area percent HPLC of any single impurity, and, incertain embodiments, no more than about 0.5 area percent HPLC of anysingle impurity, relative to the total area of the HPLC chromatogram.

The structure depicted for a form of compound 1 is also meant to includeall tautomeric forms of compound 1. Additionally, structures depictedhere are also meant to include compounds that differ only in thepresence of one or more isotopically enriched atoms. For example,compounds having the present structure except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 1 can exist in a variety of solid forms.Exemplary such forms include polymorphs such as those described herein.

As used herein, the term “polymorph” refers to the different crystalstructures into which a compound, or a salt or solvate thereof, cancrystallize.

In certain embodiments, compound 1 is a crystalline solid. In otherembodiments, compound 1 is a crystalline solid substantially free ofamorphous compound 1. As used herein, the term “substantially free ofamorphous compound 1” means that the compound contains no significantamount of amorphous compound 1. In certain embodiments, at least about95% by weight of crystalline compound 1 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 1 is present.

It has been found that compound 1 can exist in at least four distinctpolymorphic forms. In certain embodiments, the present inventionprovides a polymorphic form of compound 1 referred to herein as Form A.In certain embodiments, the present invention provides a polymorphicform of compound 1 referred to herein as Form B. In certain embodiments,the present invention provides a polymorphic form of compound 1 referredto herein as Form C. In certain embodiments, the present inventionprovides a polymorphic form of compound 1 referred to herein as Form D.

In some embodiments, compound 1 is amorphous. In some embodiments,compound 1 is amorphous, and is substantially free of crystallinecompound 1.

Form A of Compound 1

In some embodiments, Form A of compound 1 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 1 below.

TABLE 1 XRPD Peak Positions for Form A of Compound 1 Position (°2 θ) 8.69.0 11.6 14.1 15.3 15.4 17.2 18.5 20.4 20.6 21.2 21.5 21.9 22.9 23.4023.9 25.3 25.8 26.1 27.0 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 1 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.6, 17.2, and 18.5. In some embodiments, Form A ofcompound 1 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.6, 17.2,and 18.5. In some embodiments, Form A of compound 1 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.6, 17.2, and 18.5. As used herein, theterm “about”, when used in reference to a degree 2-theta value refers tothe stated value ±0.2 degree 2-theta.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 1.

Methods for preparing Form A of compound 1 are described infra.

Form B of Compound 1

In some embodiments, Form B of compound 1 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 2 below.

TABLE 2 XRPD Peak Positions for Form B of Compound 1 Position (°2 θ) 4.67.2 8.3 9.3 11.6 13.6 14.4 16.5 17.7 18.7 21.0 21.3 23.2 23.5 24.4 27.5¹ In this and all subsequent tables, the position 2 θ is within ±0.2.

In some embodiments, Form B of compound 1 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.2, 9.3, and 17.7. In some embodiments, Form B ofcompound 1 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.2, 9.3,and 17.7. In some embodiments, Form B of compound 1 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.2, 9.3 and 17.7.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 4.

Methods for preparing Form B of compound 1 are described infra.

Form C of Compound 1

In some embodiments, Form C of compound 1 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 3 below.

TABLE 3 XRPD Peak Positions for Form C of Compound 1 Position (°2 θ) 7.68.8 9.6 11.7 12.3 14.5 15.3 15.9 17.5 18.0 20.1 21.0 22.8 23.4 23.8 24.725.2 25.5 26.4 27.7 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

In some embodiments, Form C of compound 1 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.6, 15.3 and 15.9. In some embodiments, Form C ofcompound 1 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.6, 15.3and 15.9. In some embodiments, Form C of compound 1 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.6, 15.3 and 15.9.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 7.

Methods for preparing Form C of compound 1 are described infra.

Form D of Compound 1

In some embodiments, Form D of compound 1 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 4 below.

TABLE 4 XRPD Peak Positions for Form D of Compound 1 Position (°2 θ) 8.28.9 9.5 9.6 10.6 15.0 17.3 17.7 19.1 20.2 21.1 22.0 22.4 23.7 24.7 25.225.9 26.5 28.6 35.1 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

In some embodiments, Form D of compound 1 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 10.6, 15.0, and 17.3. In some embodiments, Form D ofcompound 1 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 10.6,15.0, and 17.3. In some embodiments, Form D of compound 1 ischaracterized in that it has all three peaks in its X-ray powderdiffraction pattern selected from those at about 10.6, 15.0, and 17.3.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 10.

Methods for preparing Form D of compound 1 are described infra.

In some embodiments, the present invention provides compound 1:

wherein said compound is crystalline.

In some embodiments, the present invention provides compound 1, whereinsaid compound is substantially free of amorphous compound 1.

In some embodiments, the present invention provides compound 1, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 1, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.6, about 17.2, and about 18.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.6, about 17.2, and about 18.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 1, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.1.

In some embodiments, the present invention provides compound 1, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.2, about 9.3, and about 17.7 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.2, about 9.3, and about 17.7 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 1, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.4.

In some embodiments, the present invention provides compound 1, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.6, about 15.3, and about 15.9 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.6, about 15.3, and about 15.9 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound is of Form C.

In some embodiments, the present invention provides compound 1, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.7.

In some embodiments, the present invention provides compound 1, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 10.6, about 15.0, and about 17.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound has at least two peaks in its XRPD selected from those at about10.6, about 15.0, and about 17.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 1, wherein saidcompound is of Form D.

In some embodiments, the present invention provides compound 1, whereinsaid has an XRPD substantially similar to that depicted in FIG. 10.

In some embodiments, the present invention provides a compositioncomprising compound 1 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 1 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 1 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Salt Forms of Compound 1

In some embodiments, an acid and compound 1 are ionically bonded to formone of compounds 2 through 12, described below. It is contemplated thatcompounds 2 through 12 can exist in a variety of physical forms. Forexample, compounds 2 through 12 can be in solution, suspension, or insolid form. In certain embodiments, compounds 2 through 12 are in solidform. When compounds 2 through 12 are in solid form, said compounds maybe amorphous, crystalline, or a mixture thereof. Exemplary such solidforms of compounds 2 through 12 are described in more detail below.

Compound 2 (Phosphate Salts of Compound 1)

According to one embodiment, the present invention provides a phosphatesalt of compound 1, represented by compound 2:

It will be appreciated by one of ordinary skill in the art that thephosphoric acid and compound 1 are ionically bonded to form compound 2.It is contemplated that compound 2 can exist in a variety of physicalforms. For example, compound 2 can be in solution, suspension, or insolid form. In certain embodiments, compound 2 is in solid form. Whencompound 2 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 2substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess phosphoric acid, excess compound 1, residual solvents, orany other impurities that may result from the preparation of, and/orisolation of, compound 2. In certain embodiments, at least about 95% byweight of compound 2 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 2 is present.

According to one embodiment, compound 2 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 2 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 2 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 2 is also meant to include alltautomeric forms of compound 2. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 2 can exist in a variety of solid forms.Exemplary such forms include polymorphs such as those described herein.

In certain embodiments, compound 2 is a crystalline solid. In otherembodiments, compound 2 is a crystalline solid substantially free ofamorphous compound 2. As used herein, the term “substantially free ofamorphous compound 2” means that the compound contains no significantamount of amorphous compound 2. In certain embodiments, at least about95% by weight of crystalline compound 2 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 2 is present.

It has been found that compound 2 can exist in at least four distinctpolymorphic forms. In some embodiments, the present invention provides apolymorphic form of Compound 2 referred to herein as Form A. In certainembodiments, the present invention provides a polymorphic form ofcompound 2 referred to herein as Form B. In certain embodiments, thepresent invention provides a polymorphic form of compound 2 referred toherein as Form C. In certain embodiments, the present invention providesa polymorphic form of Compound 2 referred to herein as Form D.

In some embodiments, compound 2 is amorphous. In some embodiments,compound 2 is amorphous, and is substantially free of crystallinecompound 2.

Form A of Compound 2

In some embodiments, Form A of compound 2 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 5 below.

TABLE 5 XRPD Peak Positions for Form A of Compound 2 Position (°2 θ) 5.96.3 6.8 9.8 10.1 11.1 13.8 14.4 15.4 16.0 16.6 17.3 17.9 18.9 19.2 19.720.3 20.8 21.3 22.2 23.0 23.3 23.6 24.0 24.7 25.5 26.0 26.8 27.4 27.928.4 29.2 30.5 31.3 31.8 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 2 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 6.8, 10.1, and 20.8. In some embodiments, Form A ofcompound 2 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 6.8, 10.1,and 20.8. In some embodiments, Form A of compound 2 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 6.8, 10.1, and 20.8.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 13.

Methods for preparing Form A of compound 2 are described infra.

Form B of Compound 2

In some embodiments, Form B of compound 2 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 6 below.

TABLE 6 XRPD Peak Positions for Form B of Compound 2 Position (°2 θ) 3.67.3 8.6 9.5 10.7 12.0 13.5 14.6 15.0 15.7 16.6 18.2 19.2 19.9 20.3 21.622.0 22.5 22.9 23.4 24.1 24.9 25.3 25.7 26.3 26.9 27.8 28.7 29.5 30.231.8 34.2 36.1 37.1 38.8 39.3 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form B of compound 2 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 3.6, 7.3, and 15.0. In some embodiments, Form B ofcompound 2 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 3.6, 7.3,and 15.0. In some embodiments, Form B of compound 2 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 3.6, 7.3, and 15.0.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 17.

Methods for preparing Form B of compound 2 are described infra.

Form C of Compound 2

In some embodiments, Form C of compound 2 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 7 below.

TABLE 7 XRPD Peak Positions for Form C of Compound 2 Position (°2 θ) 4.26.8 8.4 9.3 11.6 12.5 12.7 13.7 15.3 15.8 16.5 18.7 19.4 20.5 22.0 22.724.5 25.2 26.2 32.0 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

In some embodiments, Form C of compound 2 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.4, 9.3, and 16.5. In some embodiments, Form C ofcompound 2 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.4, 9.3,and 16.5. In some embodiments, Form C of compound 2 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.4, 9.3, and 16.5.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 21.

Methods for preparing Form C of compound 2 are described infra.

Form D of Compound 2

In some embodiments, Form D of compound 2 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 8 below.

TABLE 8 XRPD Peak Positions for Form D of Compound 2 Position (°2 θ) 7.18.1 9.1 10.4 10.6 11.2 12.9 13.9 15.8 16.4 17.2 17.7 18.7 19.0 20.2 20.721.0 22.1 22.7 24.5 25.1 26.4 27.4 27.8 28.7 29.1 31.0 31.5 33.8 36.337.0 38.0 ¹ In this and all subsequent tables, the position 2 θ iswithin ±0.2.

In some embodiments, Form D of compound 2 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 9.1, 10.4, and 25.1. In some embodiments, Form D ofcompound 2 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 9.1, 10.4,and 25.1. In some embodiments, Form D of compound 2 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 9.1, 10.4, and 25.1.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 25.

Methods for preparing Form D of compound 2 are described infra.

In some embodiments, the present invention provides compound 2:

In some embodiments, the present invention provides compound 2, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 2, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 2.

In some embodiments, the present invention provides compound 2, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 2, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 6.8, about 10.1, and about 20.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound has at least two peaks in its XRPD selected from those at about6.8, about 10.1, and about 20.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 2, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.13.

In some embodiments, the present invention provides compound 2, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 3.6, about 7.3, and about 15.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound has at least two peaks in its XRPD selected from those at about3.6, about 7.3, and about 15.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 2, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.17.

In some embodiments, the present invention provides compound 2, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.4, about 9.3, and about 16.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.4, about 9.3, and about 16.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound is of Form C.

In some embodiments, the present invention provides compound 2, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.21.

In some embodiments, the present invention provides compound 2, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 9.1, about 10.4, and about 25.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound has at least two peaks in its XRPD selected from those at about9.1, about 10.4, and about 25.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 2, wherein saidcompound is of Form D.

In some embodiments, the present invention provides compound 2, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.25.

In some embodiments, the present invention provides a compositioncomprising compound 2 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 2 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said compound 2 or composition thereof. In some suchembodiments, the ERK1- or ERK2-mediated disorder the disorder isselected from cancer, stroke, diabetes, hepatomegaly, cardiovasculardisease including cardiomegaly, Alzheimer's disease, cystic fibrosis,viral disease, autoimmune diseases, atherosclerosis, restenosis,psoriasis, allergic disorders including asthma, inflammation,neurological disorders and hormone-related diseases.

Compound 3 (Bisphosphate Complexes of Compound 1)

According to one embodiment, the present invention provides abisphosphate complex of compound 1, represented by compound 3:

It will be appreciated by one of ordinary skill in the art that onemolecule of phosphoric acid and compound 1 are ionically bonded, whilethe second molecule of phosphoric acid and compound 1 are likelyhydrogen bonded, to form compound 3. It is contemplated that compound 3can exist in a variety of physical forms. For example, compound 3 can bein solution, suspension, or in solid form. In certain embodiments,compound 3 is in solid form. When compound 3 is in solid form, saidcompound may be amorphous, crystalline, or a mixture thereof. Exemplarysolid forms are described in more detail below. For purposes of clarity,it will be understood that compound 3, a bisphosphate complex ofcompound 1, comprises two molecules of phosphoric acid per molecule ofcompound 1.

In some embodiments, the present invention provides compound 3substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess phosphoric acid, excess compound 1, residual solvents, orany other impurities that may result from the preparation of, and/orisolation of, compound 3. In certain embodiments, at least about 95% byweight of compound 3 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 3 is present.

According to one embodiment, compound 3 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 3 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 3 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 3 is also meant to include alltautomeric forms of compound 3. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

In certain embodiments, compound 3 is a crystalline solid. In otherembodiments, compound 3 is a crystalline solid substantially free ofamorphous compound 3. As used herein, the term “substantially free ofamorphous compound 3” means that the compound contains no significantamount of amorphous compound 3. In certain embodiments, at least about95% by weight of crystalline compound 3 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 3 is present.

It has been found that compound 3 can exist in at least one distinctcrystalline form. In some embodiments, the present invention provides acrystalline form of Compound 3 referred to herein as Form A.

In some embodiments, compound 3 is amorphous. In some embodiments,compound 3 is amorphous, and is substantially free of crystallinecompound 3.

Form A of Compound 3

In some embodiments, Form A of compound 3 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 9 below.

TABLE 9 XRPD Peak Positions for Form A of Compound 3 Position (°2 θ) 5.77.1 8.9 10.3 11.0 11.4 13.2 14.2 14.5 17.2 17.7 18.4 19.4 19.9 20.6 20.822.1 22.5 24.3 25.5 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

In some embodiments, Form A of compound 3 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.9, 10.3, and 11.0. In some embodiments, Form A ofcompound 3 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.9, 10.3,and 11.0. In some embodiments, Form A of compound 3 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.9, 10.3, and 11.0.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 28.

Methods for preparing Form A of compound 3 are described infra.

In some embodiments, the present invention provides compound 3:

In some embodiments, the present invention provides compound 3, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 3, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 3.

In some embodiments, the present invention provides compound 3, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 3, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.9, about 10.3, and about 11.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 3, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.9, about 10.3, and about 11.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 3, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 3, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.28.

In some embodiments, the present invention provides a compositioncomprising compound 3 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 3 or composition thereof. In somesuch embodiments, the present invention provides a method of treating anERK1- or ERK2-mediated disorder in a patient, comprising administeringto said patient compound 3 or composition thereof. In some suchembodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 4 (HCl Salts of Compound 1)

According to one embodiment, the present invention provides ahydrochloride salt of compound 1, represented by compound 4:

It will be appreciated by one of ordinary skill in the art that thehydrochloric acid and compound 1 are ionically bonded to form compound4. It is contemplated that compound 4 can exist in a variety of physicalforms. For example, compound 4 can be in solution, suspension, or insolid form. In certain embodiments, compound 4 is in solid form. Whencompound 4 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 4substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess hydrochloric acid, excess compound 1, residual solvents,or any other impurities that may result from the preparation of, and/orisolation of, compound 4. In certain embodiments, at least about 95% byweight of compound 4 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 4 is present.

According to one embodiment, compound 4 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 4 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 4 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 4 is also meant to include alltautomeric forms of compound 4. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 4 can exist in a variety of solid forms.Exemplary such forms include polymorphs such as those contemplated bythe present invention.

In certain embodiments, compound 4 is a crystalline solid. In otherembodiments, compound 4 is a crystalline solid substantially free ofamorphous compound 4. As used herein, the term “substantially free ofamorphous compound 4” means that the compound contains no significantamount of amorphous compound 4. In certain embodiments, at least about95% by weight of crystalline compound 4 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 4 is present.

It has been found that compound 4 can exist in at least nine distinctpolymorphic forms. In some embodiments, the present invention provides apolymorphic form of compound 4 referred to herein as Form A. In certainembodiments, the present invention provides a polymorphic form ofcompound 4 referred to herein as Form B. In certain embodiments, thepresent invention provides a polymorphic form of compound 4 referred toherein as Form C. In certain embodiments, the present invention providesa polymorphic form of compound 4 referred to herein as Form D. Incertain embodiments, the present invention provides a polymorphic formof compound 4 referred to herein as Form E. In certain embodiments, thepresent invention provides a polymorphic form of compound 4 referred toherein as Form F. In certain embodiments, the present invention providesa polymorphic form of compound 4 referred to herein as Form G. Incertain embodiments, the present invention provides a polymorphic formof compound 4 referred to herein as Form H. In certain embodiments, thepresent invention provides a polymorphic form of compound 4 referred toherein as Form I.

In some embodiments, compound 4 is amorphous. In some embodiments,compound 4 is amorphous, and is substantially free of crystallinecompound 4.

Form A of Compound 4

In some embodiments, Form A of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 10 below.

TABLE 10 XRPD Peak Positions for Form A of Compound 4 Position (°2 θ)7.5 9.3 11.2 11.9 14.2 15.0 15.3 15.7 21.4 21.9 22.6 22.8 23.4 24.6 24.825.2 26.4 26.8 30.5 34.1 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 9.3, 15.7, and 24.8. In some embodiments, Form A ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 9.3, 15.7,and 24.8. In some embodiments, Form A of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 9.3, 15.7, and 24.8.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 32.

Methods for preparing Form A of compound 4 are described infra.

Form B of Compound 4

In some embodiments, Form B of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 11 below.

TABLE 11 XRPD Peak Positions for Form B of Compound 4 Position (°2 θ)8.0 8.4 9.1 11.0 11.8 12.7 16.2 17.2 17.8 18.9 20.4 20.9 23.7 23.9 24.725.4 25.6 25.9 29.2 30.7 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form B of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.4, 12.7, and 17.8. In some embodiments, Form B ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.4, 12.7,and 17.8. In some embodiments, Form B of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.4, 12.7, and 17.8.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 36.

Methods for preparing Form B of compound 4 are described infra.

Form C of Compound 4

In some embodiments, Form C of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 12 below.

TABLE 12 XRPD Peak Positions for Form C of Compound 4 Position (°2 θ)7.7 8.2 9.0 9.5 10.2 12.1 12.4 12.6 13.5 15.3 16.4 18.4 21.0 21.3 23.123.4 23.7 24.2 25.5 25.7 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form C of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.7, 8.2, and 9.0. In some embodiments, Form C ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.7, 8.2,and 9.0. In some embodiments, Form C of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.7, 8.2, and 9.0.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 38.

Methods for preparing Form C of compound 4 are described infra.

Form D of Compound 4

In some embodiments, Form D of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 13 below.

TABLE 13 XRPD Peak Positions for Form D of Compound 4 Position (°2 θ)7.1 9.1 11.2 12.7 14.0 14.4 14.6 17.0 17.2 21.7 22.0 22.4 22.8 23.7 24.825.3 25.5 28.0 34.2 35.7 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form D of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.1, 9.1, and 11.2. In some embodiments, Form D ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.1, 9.1,and 11.2. In some embodiments, Form D of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.1, 9.1, and 11.2.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 40.

Methods for preparing Form D of compound 4 are described infra.

Form E of Compound 4

In some embodiments, Form E of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 14 below.

TABLE 14 XRPD Peak Positions for Form E of Compound 4 Position (°2 θ)7.7 9.0 10.7 14.4 15.5 17.1 18.2 19.8 20.4 21.5 23.1 24.4 24.6 25.0 27.027.3 28.1 30.9 31.2 37.6 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form E of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.7, 10.7, and 17.1. In some embodiments, Form E ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.7, 10.7,and 17.1. In some embodiments, Form E of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.7, 10.7, and 17.1.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 44.

Methods for preparing Form E of compound 4 are described infra.

Form F of Compound 4

In some embodiments, Form F of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 15 below.

TABLE 15 XRPD Peak Positions for Form F of Compound 4 Position (°2 θ)6.1 7.7 11.3 12.4 13.8 15.4 16.9 17.7 18.6 19.5 22.6 22.9 23.1 23.6 24.925.7 26.1 30.2 34.2 35.0 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form F of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 6.1, 11.3, and 18.6. In some embodiments, Form F ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 6.1, 11.3,and 18.6. In some embodiments, Form F of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 6.1, 11.3, and 18.6.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 46.

Methods for preparing Form F of compound 4 are described infra.

Form G of Compound 4

In some embodiments, Form G of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 16 below.

TABLE 16 XRPD Peak Positions for Form G of Compound 4 Position (°2 θ)5.2 8.5 8.7 10.5 14.8 15.6 19.0 19.5 20.7 21.0 21.9 22.2 23.3 25.7 27.027.4 29.6 30.7 31.3 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

In some embodiments, Form G of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 5.2, 8.7, and 19.5. In some embodiments, Form G ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 5.2, 8.7,and 19.5. In some embodiments, Form G of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 5.2, 8.7, and 19.5.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 48.

Methods for preparing Form G of compound 4 are described infra.

Form H of Compound 4

In some embodiments, Form H of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 17 below.

TABLE 17 XRPD Peak Positions for Form H of Compound 4 Position (°2 θ)7.2 8.5 9.1 10.2 13.1 14.5 15.8 18.1 18.8 20.5 21.0 21.7 22.5 23.3 24.224.6 25.3 25.8 28.8 29.9 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form H of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.5, 9.1, and 10.2. In some embodiments, Form H ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.5, 9.1,and 10.2. In some embodiments, Form H of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.5, 9.1, and 10.2.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 50.

Methods for preparing Form H of compound 4 are described infra.

Form I of Compound 4

In some embodiments, Form I of compound 4 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 18 below.

TABLE 18 XRPD Peak Positions for Form I of Compound 4 Position (°2 θ)4.7 7.1 9.3 10.8 11.9 14.1 15.0 16.7 18.8 20.3 21.1 22.2 23.1 23.5 24.225.4 26.0 29.1 ¹ In this and all subsequent tables, the position 2 θ iswithin ±0.2.

In some embodiments, Form I of compound 4 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 4.7, 7.1, and 9.3. In some embodiments, Form I ofcompound 4 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 4.7, 7.1,and 9.3. In some embodiments, Form I of compound 4 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 4.7, 7.1, and 9.3.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 52.

Methods for preparing Form I of compound 4 are described infra.

In some embodiments, the present invention provides compound 4:

In some embodiments, the present invention provides compound 4, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 4, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 4.

In some embodiments, the present invention provides compound 4, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 9.3, about 15.7, and about 24.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about9.3, about 15.7, and about 24.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.32.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.4, about 12.7, and about 17.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.4, about 12.7, and about 17.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.36.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.7, about 8.2, and about 9.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.7, about 8.2, and about 9.0 degrees 2-theta. In some such embodiments,the present invention provides compound 4, wherein said compound is ofForm C.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.38.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.1, about 9.1, and about 11.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.1, about 9.1, and about 11.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form D.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.40.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.7, about 10.7, and about 17.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.7, about 10.7, and about 17.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form E.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.44.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 6.1, about 11.3, and about 18.6 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about6.1, about 11.3, and about 18.6 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form F.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.46.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 5.2, about 8.7, and about 19.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about5.2, about 8.7, and about 19.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form G.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.48.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.5, about 9.1, and about 10.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.5, about 9.1, and about 10.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound is of Form H.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.50.

In some embodiments, the present invention provides compound 4, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 4.7, about 7.1, and about 9.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 4, wherein saidcompound has at least two peaks in its XRPD selected from those at about4.7, about 7.1, and about 9.3 degrees 2-theta. In some such embodiments,the present invention provides compound 4, wherein said compound is ofForm I.

In some embodiments, the present invention provides compound 4, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.52.

In some embodiments, the present invention provides a compositioncomprising compound 4 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 4 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 4 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 5 (HBr Salts of Compound 1)

According to one embodiment, the present invention provides ahydrobromide salt of compound 1, represented by compound 5:

It will be appreciated by one of ordinary skill in the art that thehydrobromic acid and compound 1 are ionically bonded to form compound 5.It is contemplated that compound 5 can exist in a variety of physicalforms. For example, compound 5 can be in solution, suspension, or insolid form. In certain embodiments, compound 5 is in solid form. Whencompound 5 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 5substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess hydrobromic acid, excess compound 1, residual solvents,or any other impurities that may result from the preparation of, and/orisolation of, compound 5. In certain embodiments, at least about 95% byweight of compound 5 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 5 is present.

According to one embodiment, compound 5 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 5 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 5 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 5 is also meant to include alltautomeric forms of compound 5. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 5 can exist in a variety of solid forms.Exemplary such forms include polymorphs such as those contemplated bythe present invention.

In certain embodiments, compound 5 is a crystalline solid. In otherembodiments, compound 5 is a crystalline solid substantially free ofamorphous compound 5. As used herein, the term “substantially free ofamorphous compound 5” means that the compound contains no significantamount of amorphous compound 5. In certain embodiments, at least about95% by weight of crystalline compound 5 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 5 is present.

It has been found that compound 5 can exist in at least five distinctpolymorphic forms. In some embodiments, the present invention provides apolymorphic form of compound 5 referred to herein as Form A. In certainembodiments, the present invention provides a polymorphic form ofcompound 5 referred to herein as Form B. In certain embodiments, thepresent invention provides a polymorphic form of compound 5 referred toherein as Form C. In certain embodiments, the present invention providesa polymorphic form of compound 5 referred to herein as Form D. Incertain embodiments, the present invention provides a polymorphic formof compound 5 referred to herein as Form E.

In some embodiments, compound 5 is amorphous. In some embodiments,compound 5 is amorphous, and is substantially free of crystallinecompound 5.

Form A of Compound 5

In some embodiments, Form A of compound 5 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 19 below.

TABLE 19 XRPD Peak Positions for Form A of Compound 5 Position (°2 θ)7.5 9.5 11.3 13.0 14.3 14.7 15.0 15.7 17.3 20.3 20.9 21.6 22.6 23.2 23.724.8 26.0 28.8 30.5 33.8 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 5 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 9.5, 22.6, and 24.8. In some embodiments, Form A ofcompound 5 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 9.5, 22.6,and 24.8. In some embodiments, Form A of compound 5 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 9.5, 22.6, and 24.8.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 53.

Methods for preparing Form A of compound 5 are described infra.

Form B of Compound 5

In some embodiments, Form B of compound 5 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 20 below.

TABLE 20 XRPD Peak Positions for Form B of Compound 5 Position (°2 θ)8.3 11.8 12.3 14.2 16.2 17.9 18.7 18.9 20.3 20.5 20.8 21.1 23.8 24.525.5 25.7 26.3 29.2 30.7 31.9 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form B of compound 5 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.3, 17.9, and 25.5. In some embodiments, Form B ofcompound 5 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.3, 17.9,and 25.5. In some embodiments, Form B of compound 5 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.3, 17.9, and 25.5.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 57.

Methods for preparing Form B of compound 5 are described infra.

Form C of Compound 5

In some embodiments, Form C of compound 5 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 21 below.

TABLE 21 XRPD Peak Positions for Form C of Compound 5 Position (°2 θ)7.4 8.4 10.5 15.4 15.8 17.4 20.1 20.8 22.1 22.3 22.6 23.2 24.2 24.5 25.926.6 29.0 31.8 33.8 37.7 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form C of compound 5 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.4, 8.4, and 10.5. In some embodiments, Form C ofcompound 5 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.4, 8.4,and 10.5. In some embodiments, Form C of compound 5 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.4, 8.4, and 10.5.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 59.

Methods for preparing Form C of compound 5 are described infra.

Form D of Compound 5

In some embodiments, Form D of compound 5 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 22 below.

TABLE 22 XRPD Peak Positions for Form D of Compound 5 Position (°2 θ)7.2 9.4 10.8 11.8 15.1 16.9 18.9 20.4 21.6 22.3 23.7 24.3 24.7 25.5 26.129.0 30.3 30.6 32.1 35.2 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form D of compound 5 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.2, 10.8, and 24.3. In some embodiments, Form D ofcompound 5 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.2, 10.8,and 24.3. In some embodiments, Form D of compound 5 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.2, 10.8, and 24.3.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 61.

Methods for preparing Form D of compound 5 are described infra.

Form E of Compound 5

In some embodiments, Form E of compound 5 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 23 below.

TABLE 23 XRPD Peak Positions for Form E of Compound 5 Position (°2 θ)7.8 8.7 10.0 11.6 15.0 16.4 17.5 18.7 21.5 22.8 23.8 24.3 25.2 25.8 28.829.1 30.3 31.7 33.7 36.8 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form E of compound 5 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.8, 8.7, and 16.4. In some embodiments, Form E ofcompound 5 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.8, 8.7,and 16.4. In some embodiments, Form E of compound 5 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.8, 8.7, and 16.4.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 63.

Methods for preparing Form E of compound 5 are described infra.

In some embodiments, the present invention provides compound 5:

In some embodiments, the present invention provides compound 5, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 5, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 5.

In some embodiments, the present invention provides compound 5, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 5, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 9.5 about 22.6, and about 24.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound has at least two peaks in its XRPD selected from those at about9.5, about 22.6, and about 24.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 5, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.53.

In some embodiments, the present invention provides compound 5, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.3, about 17.9, and about 25.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.3, about 17.9, and about 25.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 5, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.57.

In some embodiments, the present invention provides compound 5, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.4, about 8.4, and about 10.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.4, about 8.4, and about 10.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound is of Form C.

In some embodiments, the present invention provides compound 5, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.59.

In some embodiments, the present invention provides compound 5, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.2, about 10.8, and about 24.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.2, about 10.8, and about 24.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound is of Form D.

In some embodiments, the present invention provides compound 5, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.61.

In some embodiments, the present invention provides compound 5, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.8, about 8.7, and about 16.4 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.8, about 8.7, and about 16.4 degrees 2-theta. In some suchembodiments, the present invention provides compound 5, wherein saidcompound is of Form E.

In some embodiments, the present invention provides compound 5, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.63.

In some embodiments, the present invention provides a compositioncomprising compound 5 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 5 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 5 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 6 (Sulfate Salts of Compound 1)

According to one embodiment, the present invention provides a sulfatesalt of compound 1, represented by compound 6:

It will be appreciated by one of ordinary skill in the art that thesulfuric acid and compound 1 are ionically bonded to form compound 6. Itis contemplated that compound 6 can exist in a variety of physicalforms. For example, compound 6 can be in solution, suspension, or insolid form. In certain embodiments, compound 6 is in solid form. Whencompound 6 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 5substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess sulfuric acid, excess compound 1, residual solvents, orany other impurities that may result from the preparation of, and/orisolation of, compound 6. In certain embodiments, at least about 95% byweight of compound 6 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 6 is present.

According to one embodiment, compound 6 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 6 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 6 contains no more than about a percent HPLC ofany single impurity; no more than about 0.6 area percent HPLC of anysingle impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 6 is also meant to include alltautomeric forms of compound 6. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 6 can exist in a variety of solid forms.Exemplary such forms include polymorphs such as those contemplated bythe present invention.

In certain embodiments, compound 6 is a crystalline solid. In otherembodiments, compound 6 is a crystalline solid substantially free ofamorphous compound 6. As used herein, the term “substantially free ofamorphous compound 6” means that the compound contains no significantamount of amorphous compound 6. In certain embodiments, at least about95% by weight of crystalline compound 6 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 6 is present.

It has been found that compound 6 can exist in at least three distinctpolymorphic forms. In some embodiments, the present invention provides apolymorphic form of compound 6 referred to herein as Form A. In certainembodiments, the present invention provides a polymorphic form ofcompound 6 referred to herein as Form B. In certain embodiments, thepresent invention provides a polymorphic form of compound 6 referred toherein as Form C.

In some embodiments, compound 6 is amorphous. In some embodiments,compound 6 is amorphous, and is substantially free of crystallinecompound 6.

Form A of Compound 6

In some embodiments, Form A of compound 6 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 24 below.

TABLE 24 XRPD Peak Positions for Form A of Compound 6 Position (°2 θ)6.2 7.1 9.9 14.2 14.7 19.4 19.5 20.1 20.2 20.7 21.4 23.4 23.9 24.3 24.825.3 26.0 26.9 28.7 29.8 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 6 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 6.2, 7.1, and 21.4. In some embodiments, Form A ofcompound 6 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 6.2, 7.1,and 21.4. In some embodiments, Form A of compound 6 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 6.2, 7.1, and 21.4.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 66.

Methods for preparing Form A of compound 6 are described infra.

Form B of Compound 6

In some embodiments, Form B of compound 6 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 25 below.

TABLE 25 XRPD Peak Positions for Form B of Compound 6 Position (°2 θ)7.1 7.6 10.1 11.4 11.6 12.4 13.7 15.2 17.3 17.8 18.7 18.7 20.3 21.7 22.924.1 25.4 26.0 29.7 34.7 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form B of compound 6 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.6, 15.2, and 22.9. In some embodiments, Form B ofcompound 6 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.6, 15.2,and 22.9. In some embodiments, Form B of compound 6 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.6, 15.2, and 22.9.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 70.

Methods for preparing Form B of compound 6 are described infra.

Form C of Compound 6

In some embodiments, Form C of compound 6 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 26 below.

TABLE 26 XRPD Peak Positions for Form C of Compound 6 Position (°2 θ)7.1 7.6 8.3 9.3 12.6 13.5 14.2 17.4 18.1 19.6 20.2 20.5 20.9 21.2 23.124.4 25.1 26.2 27.9 29.9 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form C of compound 6 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.1, 7.6, and 23.1. In some embodiments, Form C ofcompound 6 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.1, 7.6,and 23.1. In some embodiments, Form C of compound 6 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.1, 7.6, and 23.1.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 72.

Methods for preparing Form C of compound 6 are described infra.

In some embodiments, the present invention provides compound 6:

In some embodiments, the present invention provides compound 6, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 6, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 6.

In some embodiments, the present invention provides compound 6, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 6, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 6.2, 7.1, about and about 21.4 degrees 2-theta. In some suchembodiments, the present invention provides compound 6, wherein saidcompound has at least two peaks in its XRPD selected from those at about6.2, 7.1, about and about 21.4 degrees 2-theta. In some suchembodiments, the present invention provides compound 6, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 6, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.66.

In some embodiments, the present invention provides compound 6, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.6, about 15.2, and about 22.9 degrees 2-theta. In some suchembodiments, the present invention provides compound 6, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.6, about 15.2, and about 22.9 degrees 2-theta. In some suchembodiments, the present invention provides compound 6, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 6, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.70.

In some embodiments, the present invention provides compound 6, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.1, about 7.6, and about 23.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 6, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.1, about 7.6, and about 23.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 6, wherein saidcompound is of Form C.

In some embodiments, the present invention provides compound 6, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.72.

In some embodiments, the present invention provides a compositioncomprising compound 6 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 6 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 6 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 7 (Bis-Sulfate Salts of Compound 1)

According to one embodiment, the present invention provides abis-sulfate salt of compound 1, represented by compound 7:

It will be appreciated by one of ordinary skill in the art that sulfuricacid and compound 1 are ionically bonded to form compound 7. It iscontemplated that compound 7 can exist in a variety of physical forms.For example, compound 7 can be in solution, suspension, or in solidform. In certain embodiments, compound 7 is in solid form. When compound7 is in solid form, said compound may be amorphous, crystalline, or amixture thereof. Exemplary solid forms are described in more detailbelow.

In some embodiments, the present invention provides compound 7substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess sulfuric acid, excess compound 1, residual solvents, orany other impurities that may result from the preparation of, and/orisolation of, compound 7. In certain embodiments, at least about 95% byweight of compound 7 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 7 is present.

According to one embodiment, compound 7 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 7 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 7 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 7 is also meant to include alltautomeric forms of compound 7. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

In certain embodiments, compound 7 is a crystalline solid. In otherembodiments, compound 7 is a crystalline solid substantially free ofamorphous compound 7. As used herein, the term “substantially free ofamorphous compound 7” means that the compound contains no significantamount of amorphous compound 7. In certain embodiments, at least about95% by weight of crystalline compound 7 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 7 is present.

It has been found that compound 7 can exist in at least one distinctcrystalline form. In some embodiments, the present invention provides acrystalline form of compound 7 referred to herein as Form A.

In some embodiments, compound 7 is amorphous. In some embodiments,compound 7 is amorphous, and is substantially free of crystallinecompound 7.

Form A of Compound 7

In some embodiments, Form A of compound 7 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 27 below.

TABLE 27 XRPD Peak Positions for Form A of Compound 7 Position (°2 θ)7.3 8.7 9.6 11.4 11.5 14.1 17.9 18.2 19.0 19.2 20.5 20.7 21.0 22.2 23.524.3 24.3 27.5 28.6 31.1 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 7 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 7.3, 8.7, and 23.5. In some embodiments, Form A ofcompound 7 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 7.3, 8.7,and 23.5. In some embodiments, Form A of compound 7 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 7.3, 8.7, and 23.5.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 74.

Methods for preparing Form A of compound 7 are described infra.

In some embodiments, the present invention provides compound 7:

In some embodiments, the present invention provides compound 7, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 7, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 7.

In some embodiments, the present invention provides compound 7, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 7, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 7.3, about 8.7, and about 23.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 7, wherein saidcompound has at least two peaks in its XRPD selected from those at about7.3, about 8.7, and about 23.5 degrees 2-theta. In some suchembodiments, the present invention provides compound 7, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 7, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.74.

In some embodiments, the present invention provides a compositioncomprising the compound 7 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 7 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 7 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 8 (Tosylate Salts of Compound 1)

According to one embodiment, the present invention provides a tosylatesalt of compound 1, represented by compound 8:

By “tosylate” is meant p-toluene sulfonate, i.e., the ionic form ofp-toluenesulfonic acid. It will be appreciated by one of ordinary skillin the art that p-toluenesulfonic acid and compound 1 are ionicallybonded to form compound 8. It is contemplated that compound 8 can existin a variety of physical forms. For example, compound 8 can be insolution, suspension, or in solid form. In certain embodiments, compound8 is in solid form. When compound 8 is in solid form, said compound maybe amorphous, crystalline, or a mixture thereof. Exemplary solid formsare described in more detail below.

In some embodiments, the present invention provides compound 8substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess p-toluenesulfonic acid, excess compound 1, residualsolvents, or any other impurities that may result from the preparationof, and/or isolation of, compound 8. In certain embodiments, at leastabout 95% by weight of compound 8 is present. In still other embodimentsof the invention, at least about 99% by weight of compound 8 is present.

According to one embodiment, compound 8 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 8 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 8 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 8 is also meant to include alltautomeric forms of compound 8. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 8 can exist in a variety of solid forms.Exemplary such forms include polymorphs and amorphous forms such asthose contemplated by the present invention.

In certain embodiments, compound 8 is a crystalline solid. In otherembodiments, compound 8 is a crystalline solid substantially free ofamorphous compound 8. As used herein, the term “substantially free ofamorphous compound 8” means that the compound contains no significantamount of amorphous compound 8. In certain embodiments, at least about95% by weight of crystalline compound 8 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 8 is present.

In certain embodiments, compound 8 is an amorphous solid. In certainembodiments, at least about 95% by weight of amorphous compound 8 ispresent. In still other embodiments of the invention, at least about 99%by weight of amorphous compound 8 is present.

It has been found that compound 8 can exist in at least four distinctforms, three of which are polymorphic and one of which is amorphous. Insome embodiments, the present invention provides a polymorphic form ofcompound 8 referred to herein as Form A. In some embodiments, thepresent invention provides a polymorphic form of compound 8 referred toherein as Form B. In some embodiments, the present invention provides apolymorphic form of compound 8 referred to herein as Form C. In someembodiments, the present invention provides an amorphous form ofcompound 8 referred to herein as Form D.

In some embodiments, compound 8 is amorphous. In some embodiments,compound 8 is amorphous, and is substantially free of crystallinecompound 8.

Form A of Compound 8

In some embodiments, Form A of compound 8 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 28 below.

TABLE 28 XRPD Peak Positions for Form A of Compound 8 Position (°2 θ)8.6 9.0 12.4 12.8 13.4 16.1 16.4 16.6 17.0 17.9 19.1 20.0 20.5 22.9 23.523.7 23.8 24.8 27.8 30.7 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 8 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 9.0, 23.8, and 24.8. In some embodiments, Form A ofcompound 8 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 9.0, 23.8,and 24.8. In some embodiments, Form A of compound 8 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 9.0, 23.8, and 24.8.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 77.

Methods for preparing Form A of compound 8 are described infra.

Form B of Compound 8

In some embodiments, Form B of compound 8 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 29 below.

TABLE 29 XRPD Peak Positions for Form B of Compound 8 Position (°2 θ)8.6 8.9 12.2 16.2 16.5 16.9 17.2 17.9 19.0 19.1 20.1 23.1 23.4 23.6 24.624.7 25.1 26.3 27.6 28.2 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form B of compound 8 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.9, 23.4, and 27.6. In some embodiments, Form B ofcompound 8 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.9, 23.4,and 27.6. In some embodiments, Form B of compound 8 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.9, 23.4, and 27.6.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 79.

Methods for preparing Form B of compound 8 are described infra.

Form C of Compound 8

In some embodiments, Form C of compound 8 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 30 below.

TABLE 30 XRPD Peak Positions for Form C of Compound 8 Peak No. Position(°2 θ) 8.8 23.1 9.5 23.8 12.5 24.2 13.3 24.6 14.2 25.2 16.9 26.3 17.430.3 17.8 31.1 18.9 31.8 20.1 38.0 ¹ In this and all subsequent tables,the position 2 θ is within ±0.2.

In some embodiments, Form C of compound 8 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.8, 16.9, and 24.2. In some embodiments, Form C ofcompound 8 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.8, 16.9,and 24.2. In some embodiments, Form C of compound 8 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.8, 16.9, and 24.2.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 81.

Methods for preparing Form C of compound 8 are described infra.

Form D of Compound 8

In some embodiments, compound 8 is an amorphous solid. For instance, insome embodiments, compound 8 is of Form D.

In certain embodiments, Form D of compound 8 is characterized by havinga DSC thermogram substantially similar to that of FIG. 84.

In certain embodiments, Form D of compound 8 is characterized by havinga TGA trace substantially similar to that of FIG. 84.

Methods for preparing Form D of compound 8 are described infra.

In some embodiments, the present invention provides compound 8:

In some embodiments, the present invention provides compound 8, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 8, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 8.

In some embodiments, the present invention provides compound 8, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 8, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 9.0, about 23.8, and about 24.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 8, wherein saidcompound has at least two peaks in its XRPD selected from those at about9.0, about 23.8, and about 24.8 degrees 2-theta. In some suchembodiments, the present invention provides compound 8, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 8, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.77.

In some embodiments, the present invention provides compound 8, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.9, about 23.4, and about 27.6 degrees 2-theta. In some suchembodiments, the present invention provides compound 8, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.9, about 23.4, and about 27.6 degrees 2-theta. In some suchembodiments, the present invention provides compound 8, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 8, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.79.

In some embodiments, the present invention provides compound 8, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.8, about 16.9, and about 24.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 8, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.8, about 16.9, and about 24.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 8, wherein saidcompound is of Form C.

In some embodiments, the present invention provides compound 8, whereinsaid compound has a XRPD substantially similar to that depicted in FIG.81.

In some embodiments, the present invention provides compound 8, whereinsaid compound has a DSC thermogram substantially similar to thatdepicted in FIG. 84. In some such embodiments, the present inventionprovides compound 8, wherein said compound is of Form D.

In some embodiments, the present invention provides a compositioncomprising compound 8 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 8 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 8 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 9 (Besylate Salts of Compound 1)

According to one embodiment, the present invention provides a besylatesalt of compound 1, represented by compound 9:

It will be appreciated by one of ordinary skill in the art thatbenzenesulfonic acid and compound 1 are ionically bonded to formcompound 9. It is contemplated that compound 9 can exist in a variety ofphysical forms. For example, compound 9 can be in solution, suspension,or in solid form. In certain embodiments, compound 9 is in solid form.When compound 9 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 9substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess benzenesulfonic acid, excess compound 1, residualsolvents, or any other impurities that may result from the preparationof, and/or isolation of, compound 9. In certain embodiments, at leastabout 95% by weight of compound 9 is present. In still other embodimentsof the invention, at least about 99% by weight of compound 9 is present.

According to one embodiment, compound 9 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 9 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 9 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 9 is also meant to include alltautomeric forms of compound 9. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 9 can exist in a variety of solid forms.Exemplary such forms include polymorphs and amorphous forms such asthose contemplated by the present invention.

In certain embodiments, compound 9 is a crystalline solid. In otherembodiments, compound 9 is a crystalline solid substantially free ofamorphous compound 9. As used herein, the term “substantially free ofamorphous compound 9” means that the compound contains no significantamount of amorphous compound 9. In certain embodiments, at least about95% by weight of crystalline compound 9 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 9 is present.

In certain embodiments, compound 9 is an amorphous solid. In certainembodiments, at least about 95% by weight of amorphous compound 9 ispresent. In still other embodiments of the invention, at least about 99%by weight of amorphous compound 9 is present.

It has been found that compound 9 can exist in at least two distinctforms, one of which is crystalline and one of which is amorphous. Insome embodiments, the present invention provides a crystalline form ofcompound 9 referred to herein as Form A. In some embodiments, thepresent invention provides an amorphous form of compound 9 referred toherein as Form B.

In some embodiments, compound 9 is amorphous. In some embodiments,compound 9 is amorphous, and is substantially free of crystallinecompound 9.

Form A of Compound 9

In some embodiments, Form A of compound 9 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 31 below.

TABLE 31 XRPD Peak Positions for Form A of Compound 9 Peak No. Position(°2 θ) 8.9 23.6 12.5 24.0 13.2 25.2 15.6 25.5 17.6 26.1 18.0 27.0 18.527.9 19.1 29.6 20.6 30.3 21.7 39.5 ¹ In this and all subsequent tables,the position 2 θ is within ±0.2.

In some embodiments, Form A of compound 9 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.9, 18.5, and 25.2. In some embodiments, Form A ofcompound 9 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.9, 18.5,and 25.2. In some embodiments, Form A of compound 9 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.9, 18.5, and 25.2.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 85.

Methods for preparing Form A of compound 9 are described infra.

Form B of Compound 9

In some embodiments, compound 9 is an amorphous solid. For instance, insome embodiments, compound 9 is of Form B.

In certain embodiments, Form B of compound 9 is characterized by havinga DSC thermogram substantially similar to that of FIG. 88.

In certain embodiments, Form B of compound 9 is characterized by havinga TGA trace substantially similar to that of FIG. 88.

Methods for preparing Form B of compound 9 are described infra.

In some embodiments, the present invention provides compound 9:

In some embodiments, the present invention provides compound 9, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 9, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 9.

In some embodiments, the present invention provides compound 9, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 9, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.9, about 18.5, and about 25.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 9, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.9, about 18.5, and about 25.2 degrees 2-theta. In some suchembodiments, the present invention provides compound 9, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 9, whereinsaid compound has a XRPD substantially similar to that depicted in FIG.85.

In some embodiments, the present invention provides compound 9, whereinsaid compound has a DSC thermogram substantially similar to thatdepicted in FIG. 88. In some such embodiments, the present inventionprovides compound 9, wherein said compound is of Form B.

In some embodiments, the present invention provides a compositioncomprising compound 9 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 9 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 9 or composition thereof. In somesuch embodiments, the ERK1- or ERK2-mediated disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.

Compound 10 (Mesylate Salts of Compound 1)

According to one embodiment, the present invention provides a mesylatesalt of compound 1, represented by compound 10:

It will be appreciated by one of ordinary skill in the art thatmethanesulfonic acid and compound 1 are ionically bonded to formcompound 10. It is contemplated that compound 10 can exist in a varietyof physical forms. For example, compound 10 can be in solution,suspension, or in solid form. In certain embodiments, compound 10 is insolid form. When compound 10 is in solid form, said compound may beamorphous, crystalline, or a mixture thereof. Exemplary solid forms aredescribed in more detail below.

In some embodiments, the present invention provides compound 10substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess methanesulfonic acid, excess compound 1, residualsolvents, or any other impurities that may result from the preparationof, and/or isolation of, compound 10. In certain embodiments, at leastabout 95% by weight of compound 10 is present. In still otherembodiments of the invention, at least about 99% by weight of compound10 is present.

According to one embodiment, compound 10 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 10 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 10 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 10 is also meant to include alltautomeric forms of compound 10. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 10 can exist in a variety of solidforms. Exemplary such forms include partially crystalline forms andamorphous forms such as those contemplated by the present invention.

In certain embodiments, compound 10 is a crystalline solid. In otherembodiments, compound 10 is a crystalline solid substantially free ofamorphous compound 10. As used herein, the term “substantially free ofamorphous compound 10” means that the compound contains no significantamount of amorphous compound 10. In certain embodiments, at least about95% by weight of crystalline compound 10 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 10 is present.

In some embodiments, compound 10 is a partially crystalline solid.

In certain embodiments, compound 10 is an amorphous solid. In certainembodiments, at least about 95% by weight of amorphous compound 10 ispresent. In still other embodiments of the invention, at least about 99%by weight of amorphous compound 10 is present.

It has been found that compound 10 can exist in at least two forms, oneof which is amorphous and the other of which is partially crystalline.In some embodiments, the present invention provides an amorphous form ofcompound 10 referred to herein as Form A. In some embodiments, thepresent invention provides a partially crystalline form of compound 10referred to herein as Form B.

In some embodiments, compound 10 is amorphous. In some embodiments,compound 10 is amorphous, and is substantially free of crystallinecompound 10.

Form A of Compound 10

In some embodiments, compound 10 is an amorphous solid. For instance, insome embodiments, compound 10 is of Form A.

In certain embodiments, Form A of compound 10 is characterized by havinga DSC thermogram substantially similar to that of FIG. 89.

In certain embodiments, Form A of compound 10 is characterized by havinga TGA trace substantially similar to that of FIG. 89.

Methods for preparing Form A of compound 10 are described infra.

Form B of Compound 10

In some embodiments, Form B of compound 10 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 32 below.

TABLE 32 XRPD Peak Positions for Form B of Compound 10 Position (°2 θ)6.1 7.9 8.3 16.3 22.6 ¹ In this and all subsequent tables, the position2 θ is within ±0.2.

In some embodiments, Form B of compound 10 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 6.1, 8.3, and 22.6. In some embodiments, Form B ofcompound 10 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 6.1, 8.3,and 22.6. In some embodiments, Form B of compound 10 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 6.1, 8.3, and 22.6.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 90.

Methods for preparing Form B of compound 10 are described infra.

In some embodiments, the present invention provides compound 10:

In some embodiments, the present invention provides compound 10, whereinsaid compound is crystalline. In some embodiments, the present inventionprovides compound 10, wherein said compound is partially crystalline.

In some embodiments, the present invention provides compound 10, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 10.

In some embodiments, the present invention provides compound 10, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 10, whereinsaid compound has a DSC thermogram substantially similar to thatdepicted in FIG. 89. In some such embodiments, the present inventionprovides compound 10, wherein said compound is of Form A.

In some embodiments, the present invention provides compound 10, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 6.1, about 8.3, and about 22.6 degrees 2-theta. In some suchembodiments, the present invention provides compound 10, wherein saidcompound has at least two peaks in its XRPD selected from those at about6.1, about 8.3, and about 22.6 degrees 2-theta. In some suchembodiments, the present invention provides compound 10, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 10, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.90.

In some embodiments, the present invention provides compound 10, whereinsaid compound has a DSC thermogram substantially similar to thatdepicted in FIG. 91.

In some embodiments, the present invention provides a compositioncomprising compound 10 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 10 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 10 or composition thereof. Insome such embodiments, the ERK1- or ERK2-mediated disorder is selectedfrom cancer, stroke, diabetes, hepatomegaly, cardiovascular diseaseincluding cardiomegaly, Alzheimer's disease, cystic fibrosis, viraldisease, autoimmune diseases, atherosclerosis, restenosis, psoriasis,allergic disorders including asthma, inflammation, neurologicaldisorders and hormone-related diseases.

Compound 11 (Maleate Salts of Compound 1)

According to one embodiment, the present invention provides a maleatesalt of compound 1, represented by compound 11:

It will be appreciated by one of ordinary skill in the art that maleicacid and compound 1 are ionically bonded to form compound 11. It iscontemplated that compound 11 can exist in a variety of physical forms.For example, compound 11 can be in solution, suspension, or in solidform. In certain embodiments, compound 11 is in solid form. Whencompound 11 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 11substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess maleic acid, excess compound 1, residual solvents, or anyother impurities that may result from the preparation of, and/orisolation of, compound 11. In certain embodiments, at least about 95% byweight of compound 11 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 11 is present.

According to one embodiment, compound 11 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 11 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 11 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 11 is also meant to include alltautomeric forms of compound 11. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

In certain embodiments, compound 11 is a crystalline solid. In otherembodiments, compound 11 is a crystalline solid substantially free ofamorphous compound 11. As used herein, the term “substantially free ofamorphous compound 11” means that the compound contains no significantamount of amorphous compound 11. In certain embodiments, at least about95% by weight of crystalline compound 11 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 11 is present.

It has been found that compound 11 can exist in at least one distinctcrystalline form. In some embodiments, the present invention provides acrystalline form of compound 11 referred to herein as Form A.

In some embodiments, compound 11 is amorphous. In some embodiments,compound 11 is amorphous, and is substantially free of crystallinecompound 11.

Form A of Compound 11

In some embodiments, Form A of compound 11 has at least 1, 2, 3, 4 or 5spectral peak(s) is or are selected from the peaks listed in Table 33below.

TABLE 33 XRPD Peak Positions for Form A of Compound 11 Position (°2 θ)5.2 8.9 9.2 10.4 12.0 13.3 13.4 15.3 16.1 18.7 20.9 23.0 23.2 23.9 24.625.6 26.1 26.3 26.7 27.0 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 11 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 8.9, 9.2, and 16.1. In some embodiments, Form A ofcompound 11 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 8.9, 9.2,and 16.1. In some embodiments, Form A of compound 11 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 8.9, 9.2, and 16.1.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 92.

Methods for preparing Form A of compound 11 are described infra.

In some embodiments, the present invention provides compound 11:

In some embodiments, the present invention provides compound 11, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 11, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 11.

In some embodiments, the present invention provides compound 11, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 11, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 8.9, about 9.2, and about 16.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 11, wherein saidcompound has at least two peaks in its XRPD selected from those at about8.9, about 9.2, and about 16.1 degrees 2-theta. In some suchembodiments, the present invention provides compound 11, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 11, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.92.

In some embodiments, the present invention provides a compositioncomprising compound 11 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 11 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 11 or composition thereof. Insome such embodiments, the ERK1- or ERK2-mediated disorder is selectedfrom cancer, stroke, diabetes, hepatomegaly, cardiovascular diseaseincluding cardiomegaly, Alzheimer's disease, cystic fibrosis, viraldisease, autoimmune diseases, atherosclerosis, restenosis, psoriasis,allergic disorders including asthma, inflammation, neurologicaldisorders and hormone-related diseases.

Compound 12 (Oxalate Salts of Compound 1)

According to one embodiment, the present invention provides an oxalatesalt of compound 1, represented by compound 12:

It will be appreciated by one of ordinary skill in the art that oxalicacid and compound 1 are ionically bonded to form compound 12. It iscontemplated that compound 12 can exist in a variety of physical forms.For example, compound 12 can be in solution, suspension, or in solidform. In certain embodiments, compound 12 is in solid form. Whencompound 12 is in solid form, said compound may be amorphous,crystalline, or a mixture thereof. Exemplary solid forms are describedin more detail below.

In some embodiments, the present invention provides compound 12substantially free of impurities. As used herein, the term“substantially free of impurities” means that the compound contains nosignificant amount of extraneous matter. Such extraneous matter mayinclude excess oxalic acid, excess compound 1, residual solvents, or anyother impurities that may result from the preparation of, and/orisolation of, compound 12. In certain embodiments, at least about 95% byweight of compound 12 is present. In still other embodiments of theinvention, at least about 99% by weight of compound 12 is present.

According to one embodiment, compound 12 is present in an amount of atleast about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent wherethe percentages are based on the total weight of the composition.According to another embodiment, compound 12 contains no more than about3.0 area percent HPLC of total organic impurities and, in certainembodiments, no more than about 1.5 area percent HPLC total organicimpurities relative to the total area of the HPLC chromatogram. In otherembodiments, compound 12 contains no more than about 1.0% area percentHPLC of any single impurity; no more than about 0.6 area percent HPLC ofany single impurity, and, in certain embodiments, no more than about 0.5area percent HPLC of any single impurity, relative to the total area ofthe HPLC chromatogram.

The structure depicted for compound 12 is also meant to include alltautomeric forms of compound 12. Additionally, structures depicted hereare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds havingthe present structure except for the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

It has been found that compound 12 can exist in a variety of solidforms. Exemplary such forms include polymorphs forms such as thosecontemplated by the present invention.

In certain embodiments, compound 12 is a crystalline solid. In otherembodiments, compound 12 is a crystalline solid substantially free ofamorphous compound 12. As used herein, the term “substantially free ofamorphous compound 12” means that the compound contains no significantamount of amorphous compound 12. In certain embodiments, at least about95% by weight of crystalline compound 12 is present. In still otherembodiments of the invention, at least about 99% by weight ofcrystalline compound 12 is present.

It has been found that compound 12 can exist in at least three distinctpolymorphic forms. In some embodiments, the present invention provides apolymorphic form of compound 12 referred to herein as Form A. In someembodiments, the present invention provides a polymorphic form ofcompound 12 referred to herein as Form B. In some embodiments, thepresent invention provides a polymorphic form of compound 12 referred toherein as Form C.

In some embodiments, compound 12 is amorphous. In some embodiments,compound 12 is amorphous, and is substantially free of crystallinecompound 12.

Form A of Compound 12

In some embodiments, Form A of compound 12 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 34 below.

TABLE 34 XRPD Peak Positions for Form A of Compound 12 Position (°2 θ)5.4 5.8 6.8 9.7 10.3 12.3 13.4 14.4 16.4 17.4 17.7 20.3 22.0 23.4 23.724.9 25.2 26.9 30.2 35.4 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form A of compound 12 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 5.4, 5.8, and 22.0. In some embodiments, Form A ofcompound 12 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 5.4, 5.8,and 22.0. In some embodiments, Form A of compound 12 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 5.4, 5.8, and 22.0.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 94.

Methods for preparing Form A of compound 12 are described infra.

Form B of Compound 12

In some embodiments, Form B of compound 12 has at least 1, 2, 3, 4 or 5spectral peak(s) selected from the peaks listed in Table 35 below.

TABLE 35 XRPD Peak Positions for Form B of Compound 12 Position (°2 θ)5.0 5.8 8.3 9.1 9.9 12.5 13.4 14.8 15.2 16.7 17.4 20.3 21.7 24.8 25.326.3 26.8 28.1 29.2 30.6 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form B of compound 12 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 5.0, 9.9, and 26.3. In some embodiments, Form B ofcompound 12 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 5.0, 9.9,and 26.3. In some embodiments, Form B of compound 12 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 5.0, 9.9, and 26.3.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 96.

Methods for preparing Form B of compound 12 are described infra.

Form C of Compound 12

In some embodiments, Form C of compound 12 has at least 1, 2, 3, 4 or 5spectral peak(s) is or are selected from the peaks listed in Table 36below.

TABLE 36 XRPD Peak Positions for Form C of Compound 12 Position (°2 θ)5.6 5.8 8.4 9.3 10.1 12.4 13.4 14.9 16.2 16.6 17.5 18.5 21.8 22.2 23.425.2 25.9 26.3 26.9 36.5 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

In some embodiments, Form C of compound 12 is characterized in that ithas one or more peaks in its X-ray powder diffraction pattern selectedfrom those at about 5.6, 5.8, and 8.4. In some embodiments, Form C ofcompound 12 is characterized in that it has two or more peaks in itsX-ray powder diffraction pattern selected from those at about 5.6, 5.8,and 8.4. In some embodiments, Form C of compound 12 is characterized inthat it has all three peaks in its X-ray powder diffraction patternselected from those at about 5.6, 5.8, and 8.4.

In certain embodiments, the X-ray powder diffraction pattern issubstantially similar to the XRPD provided in FIG. 98.

Methods for preparing Form C of compound 12 are described infra.

In some embodiments, the present invention provides compound 12:

In some embodiments, the present invention provides compound 12, whereinsaid compound is crystalline.

In some embodiments, the present invention provides compound 12, whereinsaid compound is a crystalline solid substantially free of amorphouscompound 12.

In some embodiments, the present invention provides compound 12, whereinsaid compound is substantially free of impurities.

In some embodiments, the present invention provides compound 12, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 5.4, about 5.8, and about 22.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 12, wherein saidcompound has at least two peaks in its XRPD selected from those at about5.4, about 5.8, and about 22.0 degrees 2-theta. In some suchembodiments, the present invention provides compound 12, wherein saidcompound is of Form A.

In some embodiments, the present invention provides compound 12, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.94.

In some embodiments, the present invention provides compound 12, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 5.0, about 9.9, and about 26.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 12, wherein saidcompound has at least two peaks in its XRPD selected from those at about5.0, about 9.9, and about 26.3 degrees 2-theta. In some suchembodiments, the present invention provides compound 12, wherein saidcompound is of Form B.

In some embodiments, the present invention provides compound 12, whereinsaid compound has a XRPD substantially similar to that depicted in FIG.96.

In some embodiments, the present invention provides compound 12, whereinsaid compound has one or more peaks in its XRPD selected from those atabout 5.6, about 5.8, and about 8.4 degrees 2-theta. In some suchembodiments, the present invention provides compound 12, wherein saidcompound has at least two peaks in its XRPD selected from those at about5.6, about 5.8, and about 8.4 degrees 2-theta. In some such embodiments,the present invention provides compound 12, wherein said compound is ofForm C.

In some embodiments, the present invention provides compound 12, whereinsaid compound has an XRPD substantially similar to that depicted in FIG.98.

In some embodiments, the present invention provides a compositioncomprising compound 12 and a pharmaceutically acceptable carrier orexcipient.

In some embodiments, the present invention provides a method ofinhibiting one or both of ERK1 and ERK2 in a patient comprisingadministering to said patient compound 12 or composition thereof.

In some embodiments, the present invention provides a method of treatingan ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient compound 12 or composition thereof. Insome such embodiments, the ERK1- or ERK2-mediated disorder is selectedfrom cancer, stroke, diabetes, hepatomegaly, cardiovascular diseaseincluding cardiomegaly, Alzheimer's disease, cystic fibrosis, viraldisease, autoimmune diseases, atherosclerosis, restenosis, psoriasis,allergic disorders including asthma, inflammation, neurologicaldisorders and hormone-related diseases.

In some embodiments, the present invention provides a compound selectedfrom: compound 1, Form A, compound 1, Form B, compound 1, Form C,compound 1, Form D, compound 2, Form A, compound 2, Form B, compound 2,Form C, compound 2, Form D, compound 3, Form A, compound 4, Form A,compound 4, Form B, compound 4, Form C, compound 4, Form D, compound 4,Form E, compound 4, Form F, compound 4, Form G, compound 4, Form H,compound 4, Form I, compound 5, Form A, compound 5, Form B, compound 5,Form C, compound 5, Form D, compound 5, Form E, compound 6, Form A,compound 6, Form B, compound 6, Form C, compound 7, Form A, compound 8,Form A, compound 8, Form B, compound 8, Form C, compound 8, Form D,compound 9, Form A, compound 9, Form B, compound 10, Form A, compound10, Form B, compound 11, Form A, compound 12, Form A, compound 12, FormB, and compound 12, Form C. In some such embodiments, the presentinvention provides a composition comprising one of the above compoundforms and a pharmaceutically acceptable carrier or excipient. In somesuch embodiments, the present invention provides a method of inhibitingone or both of ERK1 and ERK2 in a patient comprising administering tosaid patient one of the above compound forms or composition thereof. Insome such embodiments, the present invention provides a method oftreating an ERK1- or ERK2-mediated disorder in a patient, comprisingadministering to said patient one of the above compound forms orcomposition thereof. In some such embodiments, the ERK1- orERK2-mediated disorder is selected from cancer, stroke, diabetes,hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,atherosclerosis, restenosis, psoriasis, allergic disorders includingasthma, inflammation, neurological disorders and hormone-relateddiseases.

General Methods of Providing a Salt Compound

Compound 1 is prepared according to the methods described in detail inthe '230 publication, the entirety of which is hereby incorporatedherein by reference. Salt compounds of general formula A, which formulaencompasses, inter alia, salt compounds 2 through 12, and/or particularforms thereof, are prepared from compound 1, according to the generalScheme below.

For instance, each of compounds 2 through 12, and forms thereof, areprepared from compound 1 by combining compound 1 with an appropriateacid to form a salt of that acid. Thus, another aspect of the presentinvention provides a method for preparing compounds 2 through 12, andforms thereof.

As described generally above, in some embodiments, the present inventionprovides a method for preparing a salt compound of the general formulaA:

comprising steps of:

combining compound 1:

with a suitable acid and optionally a suitable solvent under conditionssuitable for forming a salt compound of general formula A.

In some embodiments, a suitable acid is phosphoric acid. In someembodiments, the present invention provides a method of making aphosphate salt of compound 1. In some embodiments, the phosphate salt ofcompound 1 is a monophosphate salt. In certain embodiments, thephosphate salt of compound 1 is compound 2. In certain embodiments, thephosphate salt of compound 1 is Form A of compound 2. In certainembodiments, the phosphate salt of compound 1 is Form B of compound 2.In certain embodiments, the phosphate salt of compound 1 is Form C ofcompound 2. In certain embodiments, the phosphate salt of compound 1 isForm D of compound 2. In some embodiments, the phosphate salt ofcompound 1 is a bisphosphate complex In certain embodiments, thephosphate complex of compound 1 is compound 3. In certain embodiments,the phosphate complex of compound 1 is Form A of compound 3.

In some embodiments, a suitable acid is hydrochloric acid. In someembodiments, the present invention provides a method of making ahydrochloride salt of compound 1. In certain embodiments, thehydrochloride salt of compound 1 is compound 4. In certain embodiments,the hydrochloride salt of compound 1 is Form A of compound 4. In certainembodiments, the hydrochloride salt of compound 1 is Form B of compound4. In certain embodiments, the hydrochloride salt of compound 1 is FormC of compound 4. In certain embodiments, the hydrochloride salt ofcompound 1 is Form D of compound 4. In certain embodiments, thehydrochloride salt of compound 1 is Form E of compound 4. In certainembodiments, the hydrochloride salt of compound 1 is Form F of compound4. In certain embodiments, the hydrochloride salt of compound 1 is FormG of compound 4. In certain embodiments, the hydrochloride salt ofcompound 1 is Form H of compound 4. In certain embodiments, thehydrochloride salt of compound 1 is Form I of compound 4.

In some embodiments, a suitable acid is hydrobromic acid. In someembodiments, the present invention provides a method of making ahydrobromide salt of compound 1. In certain embodiments, thehydrobromide salt of compound 1 is compound 5. In certain embodiments,the hydrobromide salt of compound 1 is Form A of compound 5. In certainembodiments, the hydrobromide salt of compound 1 is Form B of compound5. In certain embodiments, the hydrobromide salt of compound 1 is Form Cof compound 5. In certain embodiments, the hydrobromide salt of compound1 is Form D of compound 5. In certain embodiments, the hydrobromide saltof compound 1 is Form E of compound 5.

In some embodiments, a suitable acid is sulfuric acid. In someembodiments, the present invention provides a method of making a sulfatesalt of compound 1. In some embodiments, the sulfate salt of compound 1is a monosulfate salt. In certain embodiments, the sulfate salt ofcompound 1 is compound 6. In certain embodiments, the sulfate salt ofcompound 1 is Form A of compound 6. In certain embodiments, the sulfatesalt of compound 1 is Form B of compound 6. In certain embodiments, thesulfate salt of compound 1 is Form C of compound 6. In some embodiments,the sulfate salt of compound 1 is a bis-sulfate salt. In certainembodiments, the sulfate salt of compound 1 is compound 7. In certainembodiments, the phosphate salt of compound 1 is Form A of compound 7.

In some embodiments, a suitable acid is p-toluenesulfonic acid. In someembodiments, the present invention provides a method of making atosylate salt of compound 1. In certain embodiments, the tosylate saltof compound 1 is compound 8. In certain embodiments, the tosylate saltof compound 1 is Form A of compound 8. In certain embodiments, thetosylate salt of compound 1 is Form B of compound 8. In certainembodiments, the tosylate salt of compound 1 is Form C of compound 8. Incertain embodiments, the tosylate salt of compound 1 is Form D ofcompound 8.

In some embodiments, a suitable acid is benzenesulfonic acid. In someembodiments, the present invention provides a method of making abesylate salt of compound 1. In certain embodiments, the besylate saltof compound 1 is compound 9. In certain embodiments, the besylate saltof compound 1 is Form A of compound 9. In certain embodiments, thebesylate salt of compound 1 is Form B of compound 9.

In some embodiments, a suitable acid is methanesulfonic acid. In someembodiments, the present invention provides a method of making amesylate salt of compound 1. In certain embodiments, the mesylate saltof compound 1 is compound 10. In certain embodiments, the mesylate saltof compound 1 is Form A of compound 10. In certain embodiments, themesylate salt of compound 1 is Form B of compound 10.

In some embodiments, a suitable acid is maleic acid. In someembodiments, the present invention provides a method of making a maleatesalt of compound 1. In certain embodiments, the maleate salt of compound1 is compound 11. In certain embodiments, the maleate salt of compound 1is Form A of compound 11.

In some embodiments, a suitable acid is oxalic acid. In someembodiments, the present invention provides a method of making anoxalate salt of compound 1. In certain embodiments, the oxalate salt ofcompound 1 is compound 12. In certain embodiments, the oxalate salt ofcompound 1 is Form A of compound 12. In certain embodiments, the oxalatesalt of compound 1 is Form B of compound 12. In certain embodiments, theoxalate salt of compound 1 is Form C of compound 12.

A suitable solvent may be any solvent system (e.g., one solvent or amixture of solvents) in which compound 1 and/or an acid are soluble, orare at least partially soluble.

Examples of suitable solvents useful in the present invention include,but are not limited to protic solvents, aprotic solvents, polar aproticsolvent, or mixtures thereof. In certain embodiments, suitable solventsinclude an ether, an ester, an alcohol, a ketone, or a mixture thereof.In some embodiments, the solvent is one or more organic alcohols. Insome embodiments, the solvent is chlorinated. In some embodiments, thesolvent is an aromatic solvent.

In certain embodiments, a suitable solvent is methanol, ethanol,isopropanol, or acetone wherein said solvent is anhydrous or incombination with water or heptane. In some embodiments, suitablesolvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide,glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, andacetonitrile. In some embodiments, a suitable solvent is ethanol. Insome embodiments, a suitable solvent is anhydrous ethanol. In someembodiments, the suitable solvent is MTBE.

In some embodiments, a suitable solvent is ethyl acetate. In someembodiments, a suitable solvent is a mixture of methanol and methylenechloride. In some embodiments, a suitable solvent is a mixture ofacetonitrile and water. In certain embodiments, a suitable solvent ismethyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. Incertain embodiments, a suitable solvent is diethylether. In certainembodiments, a suitable solvent is water. In certain embodiments, asuitable solvent is methyl ethyl ketone. In certain embodiments, asuitable solvent is toluene.

In some embodiments, the present invention provides a method forpreparing a salt compound of the general formula A, comprising one ormore steps of removing a solvent and adding a solvent. In someembodiments, an added solvent is the same as the solvent removed. Insome embodiments, an added solvent is different from the solventremoved. Means of solvent removal are known in the synthetic andchemical arts and include, but are not limited to, any of thosedescribed herein and in the Exemplification.

In some embodiments, a method for preparing a salt compound of thegeneral formula A comprises one or more steps of heating or cooling apreparation.

In some embodiments, a method for preparing a salt compound of thegeneral formula A comprises one or more steps of agitating or stirring apreparation.

In some embodiments, a method for preparing a salt compound of thegeneral formula A comprises a step of adding a suitable acid to asolution or slurry of compound 1.

In some embodiments, a method for preparing a salt compound of thegeneral formula A comprises a step of heating.

In certain embodiments, a salt compound of formula A precipitates fromthe mixture. In another embodiment, a salt compound of formula Acrystallizes from the mixture. In other embodiments, a salt compound offormula A crystallizes from solution following seeding of the solution(i.e., adding crystals of a salt compound of formula A to the solution).

A salt compound of formula A can precipitate out of the reactionmixture, or be generated by removal of part or all of the solventthrough methods such as evaporation, distillation, filtration (ex.nanofiltration, ultrafiltration), reverse osmosis, absorption andreaction, by adding an anti-solvent such as heptane, by cooling or bydifferent combinations of these methods.

As described generally above, a salt compound of formula A is optionallyisolated. It will be appreciated that a salt compound of formula A maybe isolated by any suitable physical means known to one of ordinaryskill in the art. In certain embodiments, precipitated solid saltcompound of formula A is separated from the supernatant by filtration.In other embodiments, precipitated solid salt compound of formula A isseparated from the supernatant by decanting the supernatant.

In certain embodiments, a salt compound of formula A is separated fromthe supernatant by filtration.

In certain embodiments, an isolated salt compound of formula A is driedin air. In other embodiments isolated Compound 2 is dried under reducedpressure, optionally at elevated temperature.

Uses of Compounds and Pharmaceutically Acceptable Compositions

As described generally above, compound 1, and pharmaceuticallyacceptable salts thereof described herein, is an inhibitor of one orboth of ERK1 and ERK2. One of ordinary skill in the art will recognizethat ERK is one of the key components in the RAS-RAF-MEK-ERK MAPKpathway and that ERK1 and ERK2 are downstream nodes within the MAPKpathway. Without wishing to be bound by theory, because of thedownstream location of ERK1 and ERK1 in the MAPK pathway, an ERKinhibitor can treat disease or disorders in which activation of the MAPKpathway at any level (Ras-Raf-Mek-ERK) is known or suspected to play arole, including one or both of ERK1 and ERK2 as well as other nodes inthe MAPK pathway upstream from ERK (such as Ras, Raf and Mek).Furthermore, because ERK is a downstream target, ERK inhibitors arebelieved to be able to overcome, in some instances, drug resistanceinduced by inhibitors of targets upstream of ERK within the MAPKpathway. For example, small molecule inhibitors of RAF or MEK utilizedin the treatment of K-RAS and B-RAF mutant tumors have resulted in suchdrug resistance. Similarly, drug resistance has been associated withother tumors driven by hyperactivation of the MAPK pathway (such as NF 1mutant tumors). Kinase selectivity was achieved through silencing theselective Cys in a combination of the interactions between the covalentinhibitors of the invention and unique amino acids in the ATP bindingpocket. Targeting the selective Cys provides for prolongedpharmacodynamics in silencing ERK activity, as well as potential lowerdoses in cancer treatment, compared to reversible inhibitors.

The activity of compound 1, and pharmaceutically acceptable saltsthereof, as an inhibitor of one or both of an ERK1 and ERK2 kinase, or amutant thereof, may be assayed in vitro, in vivo or in a cell line. Invitro assays include assays that determine inhibition of downstreamphosphorylation, changes in gene expression, subsequent functionalmarkers and consequences, and/or kinase activity of one or both ofactivated ERK1 and ERK2 kinase, or a mutant thereof. Alternate in vitroassays quantitate the ability of the test compound to bind to one orboth of ERK1 and ERK2. Test compound binding may be measured byradiolabeling the test compound prior to binding, isolating one or bothof the compound/ERK1 complex and the compound/ERK2 complex, anddetermining the amount of radiolabel bound. Alternatively, test compoundbinding may be determined by running a competition experiment where testcompounds are incubated with one or both of ERK1 and ERK2 kinase boundto known radioligands. Test compound binding may be determined bycompetition with an ERK covalent probe that is amenable to furtherfunctionalization with a detection probe, such as, for example, afluorophore, biotin conjugate, radiolabel, or any other probe thatfacilitates its quantification. Detailed conditions for assaying acompound utilized in this invention as an inhibitor of one or both ofERK1 and ERK2, or a mutant thereof, are also set forth below and/or inthe Examples of the '230 publication.

The term “measurably inhibit”, as used herein means a measurable changein one or both of ERK1 and ERK2 protein kinase activity between a samplecomprising a provided composition, and one or both of an ERK1 and ERK2protein kinase and an equivalent sample comprising one or both of ERK1and ERK2 protein kinase in the absence of a provided composition. Suchmeasurements of protein kinase activity are known to one of ordinaryskill in the art and include those methods set forth herein below and/orin the Examples of the '230 publication.

As described above, in some embodiments, compound 1, andpharmaceutically acceptable salts thereof, is an inhibitor of one orboth of ERK1 and ERK2 protein kinases, and ERK1 and ERK2 are downstreamtargets within the MAPK pathway. Without wishing to be bound by anyparticular theory, such compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder in which activation of the MAPK pathway at any level(Ras-Raf-Mek-ERK) is known or suspected to play a role. Such disease,condition, or disorder may be referred to herein as associated with theMAPK pathway or alternatively as associated with one or both of ERK1 andERK2. Such diseases, conditions, or disorders may also be referred toherein as an “ERK1- or ERK2-mediated disease, condition, or disorder.”

In some embodiments, the present invention provides a method fortreating or lessening the severity of a disease, condition, or disorderwhere activation of the MAPK pathway (at any level in Ras-Raf-Mek-ERK),including one or both of ERK1 and ERK2 protein kinases, is implicated insaid disease, condition, or disorder, wherein said method comprisesadministering to a patient in need thereof a compound of the presentinvention.

In some embodiments, the present invention relates to a method ofinhibiting one or both of ERK1 and ERK2 protein kinase activity in apatient comprising the step of administering to said patient acomposition comprising a compound of the present invention.

In other embodiments, the present invention provides a method fortreating a disease, condition, or disorder mediated by one or both ofERK1 and ERK2 kinase, or a mutant thereof, in a patient in need thereof,comprising the step of administering to said patient a compound of thepresent invention.

In certain embodiments, the present invention provides a method forovercoming drug resistance to Raf or MEK inhibitors, comprising the stepof administering to a patient an inhibitor compound of one or both ofERK1 and ERK2, such as a compound of the present invention. In certainembodiments, the mechanism of drug resistance is through mutation of atarget protein or reactivation of the MAPK pathway.

As used herein, the term “resistance” may refer to changes in awild-type nucleic acid sequence coding a target protein, and/or to theamino acid sequence of the target protein and/or to the amino acidsequence of another protein, which changes, decreases or abolishes theinhibitory effect of the inhibitor on the target protein. The term“resistance” may also refer to overexpression or silencing of a proteindiffering from a target protein that can reactivate the MAPK pathway orother survival pathways.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent, delay or lessen theseverity of their recurrence.

In some embodiments, the present invention provides a method oftreating, stabilizing or lessening the severity or progression of one ormore diseases or disorders associated with one or both of ERK1 and ERK2comprising administering to a patient in need thereof a compositioncomprising a compound of the present invention.

General diseases, conditions, or disorders treated by a compound of thepresent invention include cancer, an autoimmune disorder, aneurodegenerative or neurological disorder, liver disease, a cardiacdisorder, schizophrenia, or a bone-related disorder.

In some embodiments, the present invention relates to a method oftreating or lessening the severity of a disease, condition, or disorderselected from cancer, stroke, diabetes, hepatomegaly, cardiovasculardisease including cardiomegaly, Alzheimer's disease, cystic fibrosis,viral disease, autoimmune diseases, atherosclerosis, restenosis,psoriasis, allergic disorders including asthma, inflammation,neurological disorders and hormone-related diseases, wherein the methodcomprises administering to a patient in need thereof a compositioncomprising a compound of the present invention.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention. In some embodiments, the cancer is recurring. Incertain embodiments, the cancer is refractory. In some embodiments, thecancer is metastatic. In some embodiments, the cancer is locallyadvanced.

In certain embodiments, the cancer is a RAF inhibitor-resistant cancer.In some such embodiments, the RAF inhibitor-resistant cancer is a BRAFinhibitor-resistant cancer.

In certain embodiments, the cancer is a MEK inhibitor-resistant cancer.

In certain embodiments, the cancer is a MAPK pathway-mediated cancer.

In some embodiments, the cancer is a BRAF-mutated cancer. In certainembodiments, the BRAF-mutated cancer is a BRAF^(V600)-mutated cancer,such as BRAF^(V600E) BRAF^(V600K), BRAF^(V600R), and BRAF^(V600D).

In some embodiments, the cancer is a RAS-mutated cancer. In certainembodiments, the RAS-mutated involves codons 12, 13, or 61. In certainembodiments, the RAS-mutated cancer is a KRAS-mutated cancer, including,but not limited to, KRAS^(G12C/D/V), KRAS^(G13C/D), or KRAS^(Q61L/H/R).In certain embodiments, the RAS-mutated cancer is an NRAS-mutatedcancer, including, but not limited to, NRAS^(Q61R), NRAS^(Q61K),NRAS^(Q61L), or NRAS^(Q61H). In certain embodiments, the RAS-mutatedcancer is an HRAS-mutated cancer, including, but not limited to,HRAS^(G12V), HRAS^(Q61R), and HRAS^(G12S).

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is selected from multiple myeloma,breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus,larynx, glioblastoma, neuroblastoma, stomach (gastric), skin,keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, smallcell carcinoma, lung, bone, colon, thyroid, adenoma, pancreas,adenocarcinoma, thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma, seminoma, melanoma (including uvealmelanoma) sarcoma, bladder carcinoma, liver carcinoma (e.g.,hepatocellular carcinoma (HCC)) and biliary passage carcinoma), kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colorectal carcinoma, large intestine, rectum, brainand central nervous system, endometrial, multiple myeloma (MM),prostate, AML, and leukemia. In some such embodiments, the cancer isrelapsed. In some embodiments, the cancer is refractory. In someembodiments, the cancer is locally advanced. In some embodiments, thecancer is metastatic.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is selected from carcinoma,lymphoma, blastoma, sarcoma, and leukemia. In some embodiments, asarcoma is a soft tissue sarcoma. In some embodiments, a lymphoma isnon-hodgkins lymphoma. In some embodiments, a lymphoma is large cellimmunoblastic lymphoma. In some embodiments, the cancer is selected fromadenocarcinoma; adenoma; adrenocortical cancer; bladder cancer; bonecancer; brain cancer; breast cancer; cancer of the buccal cavity;cervical cancer; colon cancer; colorectal cancer; endometrial or uterinecarcinoma; epidermoid carcinoma; esophogeal cancer; eye cancer;follicular carcinoma; gallbladder cancer; prostate, AML, multiplemyeloma (MM), gastrointestinal cancer, such as, for example,gastrointestinal stromal tumor; cancer of the genitourinary tract;glioblastoma; hairy cell carcinoma; various types of head and neckcancer; hepatic carcinoma; hepatocellular cancer; Hodgkin's disease;keratoacanthoma; kidney cancer; large cell carcinoma; cancer of thelarge intestine; laryngeal cancer; liver cancer; lung cancer, such as,for example, adenocarcinoma of the lung, anaplastic carcinoma of thelung, papillary lung adenocarcinoma, small-cell lung cancer, squamouscarcinoma of the lung, non-small cell lung cancer; melanoma andnonmelanoma skin cancer; lymphoid disorders; myeloproliferativedisorders, such as, for example, polycythemia vera, essentialthrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasiawith myelofibrosis, chronic myeloid leukemia (CML), chronicmyelomonocytic leukemia, chronic eosinophilic leukemia, chroniclymphocytic leukemia (CLL), hypereosinophilic syndrome, systematic mastcell disease, atypical CML, AML, or juvenile myelomonocytic leukemia;plasmacytoma; multiple myeloma; neuroblastoma; ovarian cancer; papillarycarcinoma; pancreatic cancer; cancer of the peritoneum; prostate cancer,including benign prostatic hyperplasia; rectal cancer; salivary glandcarcinoma; sarcoma; seminoma; squamous cell cancer; small cellcarcinoma; cancer of the small intestine; stomach cancer; testicularcancer; thyroid cancer; undifferentiated carcinoma; and vulval cancer.In some such embodiments, the cancer is relapsed. In some embodiments,the cancer is refractory. In some embodiments, the cancer is locallyadvanced. In some embodiments, the cancer is metastatic.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is selected from melanoma,pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer (e.g.,non-small cell lung cancer), breast cancer, endometrial cancer, prostatecancer, ovarian cancer, hepatocellular carcinoma (HCC), multiple myeloma(MM), and leukemia. In some embodiments, a leukemia is an acuteleukemia. In certain embodiments, a leukemia is acute myeloid leukemia.In certain embodiments, a leukemia is acute lymphoblastic leukemia.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is selected from melanoma,colorectal cancer, lung cancer, or pancreatic.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is melanoma. In certainembodiments, the melanoma is uveal melanoma. In some embodiments, themelanoma is a melanoma of the skin. In certain embodiments, the melanomais locally advanced. In some embodiments, the melanoma is metastatic. Insome embodiments, the melanoma is recurring. In some embodiments, themelanoma is BRAF^(v6)° °-mutated melanoma. In certain embodiments, themelanoma is a RAS-mutated melanoma. In some embodiments, the melanoma isNRAS-mutated melanoma. In certain embodiments, the melanoma is wild typefor KRAS, NRAS or BRAF. In certain embodiments, the melanoma is a BRAFinhibitor-resistant (e.g., Vemurfenib-resistant, dabrafenib-resistant,etc.) melanoma. In certain embodiments, the cancer is a VemR (i.e.,Vemurfenib-resistant) BRAF-mutated melanoma. In some embodiments, themelanoma is relapsed. In some embodiments, the melanoma is refractory.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is colorectal cancer. In certainembodiments, the colorectal cancer is locally advanced. In certainembodiments, the colorectal cancer is metastatic. In certainembodiments, the colorectal cancer is a BRAF-mutated colorectal cancer.In certain embodiments, the colorectal cancer is a BRAF^(v600)-mutatedcolorectal cancer. In certain embodiments, the colorectal cancer is aRAS-mutated colorectal cancer. In certain embodiments, the colorectalcancer is a KRAS-mutated colorectal cancer. In certain embodiments, thecolorectal cancer is a NRAS-mutated colorectal cancer. In someembodiments, the colorectal cancer is relapsed. In some embodiments, thecolorectal cancer is refractory.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is pancreatic cancer. In certainembodiments, the pancreatic cancer is locally advanced. In certainembodiments, the pancreatic cancer is metastatic. In certainembodiments, the pancreatic cancer is a pancreatic ductal adenocarcinoma(PDAC). In certain embodiments, the pancreatic cancer is a RAS-mutatedpancreatic cancer. In certain embodiments, the pancreatic cancer is aKRAS-mutated pancreatic cancer. In certain embodiments, the pancreaticcancer is KRAS-mutated pancreatic cancer, including, but not limited to,KRAS^(G12C/D/V), KRAS^(G13C/D), or KRAS^(Q61L/H/R). In some embodiments,the pancreatic cancer is relapsed. In some embodiments, the pancreaticcancer is refractory.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is a papillary thyroid cancer. Incertain embodiments, the papillary thyroid cancer is locally advanced.In some embodiments, the papillary thyroid cancer is metastatic. In someembodiments, the papillary thyroid cancer is recurring. In someembodiments, the papillary thyroid cancer is BRAF-mutated papillarythyroid cancer. In some embodiments, the papillary thyroid cancer isBRAF^(v600)-mutated papillary thyroid cancer. In some embodiments, thepapillary thyroid cancer is relapsed. In some embodiments, the papillarythyroid cancer is refractory. In some embodiments, the papillary thyroidcancer includes undifferentiated or dedifferentiated histology.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is lung cancer. In certainembodiments, the lung cancer is non-small cell lung cancer (NSCLC). Incertain embodiments, the lung cancer is locally advanced. In certainembodiments, the lung cancer is metastatic. In certain embodiments, thelung cancer is a RAS-mutated lung cancer. In certain embodiments, thelung cancer is KRAS-mutated lung cancer. In certain embodiments, thelung cancer is a KRAS-mutated lung cancer, including, but not limitedto, KRAS^(G12C/D/V), KRAS^(G13C/D), KRAS^(Q61L/H/R). In someembodiments, the lung cancer is relapsed. In some embodiments, the lungcancer is refractory.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is a leukemia. In someembodiments, a leukemia is a chronic leukemia. In certain embodiments, aleukemia is chronic myeloid leukemia. In some embodiments, a leukemia isan acute leukemia. In certain embodiments, a leukemia is acute myeloidleukemia (AML). In certain embodiments, a leukemia is acute monocyticleukemia (AMoL, or AML-M5). In certain embodiments, a leukemia is acutelymphoblastic leukemia (ALL). In certain embodiments, a leukemia isacute T cell leukemia. In certain embodiments, a leukemia ismyelomonoblastic leukemia. In certain embodiments, a leukemia is human Bcell precursor leukemia. In certain embodiments, a leukemia has a Flt3mutation or rearrangement. In some embodiments, the leukemia isrelapsed. In some embodiments, the leukemia is refractory.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is a CNS cancer, for instance CNStumors. In certain embodiments, a CNS tumor is a glioblastoma orglioblastoma multiforme (GBM). In some embodiments, the presentinvention relates to a method of treating stomach (gastric) andesophageal tumors and cancers.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is multiple myeloma (MM). Incertain embodiments, the multiple myeloma is locally advanced. Incertain embodiments, the multiple myeloma is metastatic. In certainembodiments, the multiple myeloma is a RAS-mutated multiple myeloma. Incertain embodiments, the multiple myeloma is KRAS-mutated multiplemyeloma. In certain embodiments, the multiple myeloma is a KRAS-mutatedmultiple myeloma, including, but not limited to, KRAS^(G12C/D/V),KRAS^(G13C/D), or KRAS^(Q61L/H/R). In some embodiments, the multiplemyeloma is relapsed. In some embodiments, the multiple myeloma isrefractory.

In some embodiments, the present invention relates to a method oftreating a cancer, wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is hepatocellular carcinoma (HCC).In certain embodiments, the HCC is locally advanced. In certainembodiments, the HCC is metastatic. In certain embodiments, the HCC is aRAS-mutated HCC. In certain embodiments, the HCC is KRAS-mutated HCC. Incertain embodiments, the HCC is a KRAS-mutated HCC, including, but notlimited to, KRAS^(G12C/D/V), KRAS^(G13C/D), or KRAS^(Q61L/H/R). In someembodiments, the hepatocellular carcinoma is relapsed. In someembodiments, the hepatocellular carcinoma is refractory.

In some embodiments, the present invention relates to a method oftreating a cancer wherein the method comprises administering to apatient in need thereof a composition comprising a compound of thepresent invention, wherein the cancer is selected from breast,colorectal, endometrial, hematological, leukemia (e.g., AML), liver,lung, melanoma, ovarian, pancreatic, prostate, or thyroid.

Pharmaceutically Acceptable Compositions

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting one or both of ERK 1 and ERK2 kinase, or a mutant thereof,activity in a biological sample comprising the step of contacting saidbiological sample with a compound of this invention, or a compositioncomprising said compound. In certain embodiments, the invention relatesto a method of irreversibly inhibiting one or both of ERK1 and ERK2kinase, or a mutant thereof, activity in a biological sample comprisingthe step of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or both of ERK1 and ERK2, or a mutant thereof,activity in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ-transplantation,biological specimen storage, and biological assays.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting one or both of ERK1 and ERK2 kinase, or a mutant thereof,activity in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound. According to certain embodiments, the invention relatesto a method of irreversibly inhibiting one or both of ERK1 and ERK2kinase, or a mutant thereof, activity in a patient comprising the stepof administering to said patient a compound of the present invention, ora composition comprising said compound. In certain embodiments, theactivity is inhibited irreversibly by covalently modifying Cys 183 ofERK1. In certain embodiments, the activity is inhibited irreversibly bycovalently modifying Cys 166 of ERK2. In certain embodiments, theactivity is inhibited irreversibly by covalently modifying Cys 183 ofERK1 and Cys 166 of ERK2. In other embodiments, the present inventionprovides a method for treating a disease, disorder, or conditionmediated by one or both of ERK1 and ERK2 kinase, or a mutant thereof, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

All features of each of the aspects of the invention apply to all otheraspects mutatis mutandis. Each of the references referred to herein,including but not limited to patents, patent applications and journalarticles, is incorporated by reference herein as though fully set forthin its entirety.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

General Procedures

X-ray powder diffraction patterns were collected on one of twoinstruments, a PANalytical Empyrean X-ray powder diffractometer or aRigaku XRD, both with CuKα radiation. The PANalytical Empyreaninstrument was equipped with a fine focus X-ray tube. The voltage andamperage of the X-ray generator were set at 45 kV and 40 mA,respectively. The divergence slits were set at 1/16° and ⅛°, and thereceiving slits were set at 1/16°. Diffracted radiation was measuredusing a Pixel 2D detector. A theta-two theta continuous scan was set atstep size 0.013 or 0.026 from 3° to 40° 2θ with sample spinning rate of4. A sintered alumina standard was used to check the peak positions. Thediffraction patterns measured on the Rigaku system were obtained on aRigaku XRD; SmartLab with Cu-Kα radiation and D/teX Ultra detector.

The powder samples were deposited on a zero-background polished siliconsample holder and were spun during measurement. Measurements wereperformed as follows: 40 kV/44 mA tube power, 0.02° 2θ step size, 4 or5° 2θ/min, and 3-40° 2θ scanning range.

Proton Nuclear Magnetic Resonance (¹H NMR) spectra were obtained on aBruker AVANCE-300 MHz NMR spectrometer. Deuterated DMSO was used assolvent.

DSC data was obtained on a TA Instruments Q1000, Q2000, or DiscoverSeries DSC. Samples were weighed into aluminum pans, crimped with pinhole aluminum lids, and heated at a rate of 10° C./min. Indium was usedas the calibration standard.

TGA analyses were performed on a TA instruments Q500 or Discovery SeriesTGA. About 2 to 10 mg were added to an aluminum sample pan and heated ata rate of 10° C./min.

TGA/DSC data was obtained on a Mettler Toledo TGA/DSC 1 Star System. Thesamples were loaded on a aluminum sample pan and heated at a rate of 10°C./min.

Hygroscopicity was determined on a Surface Measurement Systems DVS-1 orDVS-Advantage Dynamic Vapor Sorption analyzer. A typical sample size of5 to 20 mg was loaded into the DVS instrument sample pan and the samplewas analyzed on a DVS automated sorption analyzer at room temperature.The relative humidity (RH) was increased from 0 or 5% to 90 or 95% RH at5 or 10% RH steps. The RH was then decreased in a similar manner toaccomplish a full absorption/desorption cycle. In some cases a secondabsorption/desorption cycle was performed.

Example A General Preparation of Compound 1

The title compound was prepared according to the steps and intermediatesdescribed below and in the '230 publication, the entirety of which isincorporated herein by reference.

Step 1:N-(2-(2-Chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)5-methylphenyl)acrylamide(Intermediate 1)

To a stirred solution of N-(2-amino-5-methylphenyl)acrylamide (22.2mmol) in dimethyl acetamide (25 mL) was added potassium carbonate (46.0mmol) at rt, and the mixture was stirred for 15 minutes. To thisreaction mixture, 2,4-dichloro-5-trifluoromethylpyrimidine (22.2 mmol)was added, and the stirring continued at 60° C. for 1 h. Uponcompletion, the reaction mixture was diluted with water (2×50 mL) andextracted with EtOAc (2×100 mL). The organic layer was dried over sodiumsulfate and concentrated to get the crude product. This crude waspurified by silica gel column chromatography and subsequently purifiedby prep-HPLC to get desired intermediate 1.

Step 2: Acid Catalyzed Coupling Method

To a solution of Intermediate 1 (2.923 mmol) in 0.04 M PTSA solution in1,4-dioxane (20 mL) was added 2-methoxy-5-methylpyridin-4-amine (3.5076mmol), and the mixture was stirred at 95° C. for 16 h. Upon completion,the reaction mixture was directly absorbed on silica gel and purified bycolumn chromatography. The resulting product was stirred in a mixture ofDCM:EtOAc:diethyl ether (10 mL:10 mL:30 mL) for 10 min, then filteredand dried under vacuum to obtain the desired compound.

MS m/z 459.2 (ES+, M+H). ¹HNMR (DMSO-d₆) δ 2.10 (s, 3H), 2.32 (s, 3H),3.75 (s, 3H), 5.78 (dd, 1H, J=2.0, 10.0 Hz), 6.28 (dd, 1H, J=2.0, 16.8Hz), 6.45 (dd, 1H, J=10.6, 16.8 Hz), 7.09 (br t, 3H, J=8.0 Hz), 7.50 (d,1H, J=8.4 Hz), 7.79 (s, 1H), 8.36 (s, 2H), 8.72 (s, 1H), 10.25 (s, 1H).

Alternative Step 2: Pd-Catalyzed Coupling Method

Alternatively, Step 2 can be carried out by adding Intermediate 1 to asuitable coupling partner in the presence of Na₂CO₃, a degassed solvent(e.g., tert-amyl alcohol), a suitable palladium catalyst (e.g.,tris-dibenzylamino dipalladium) and a suitable phosphine ligand (e.g.,Dave Phos) under conditions suitable to effect coupling.

Example 1 Preparation of Free Base Forms A-D of Compound 1

Compound 1 is prepared according to the method described in detail inExample 94 of the '230 publication, the entirety of which is herebyincorporated herein by reference.

Form A of Compound 1

Form A of compound 1 was prepared as follows.

Procedure A: Form B of compound 1 was slurried in ethyl acetate at 30°C. After overnight vigorous stirring, the reaction was filtered anddried.

Procedure B: Form B of compound 1 was heated to a temperature of 170°C., then cooled to room temperature. Solids converted to Form A at atemperature of 145° C.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A.

Table 1, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form A of compound 1.

TABLE 1 XRPD Peak Positions for Form A of Compound 1 Position (°2 θ) 8.69.0 11.6 14.1 15.3 15.4 17.2 18.5 20.4 20.6 21.2 21.5 21.9 22.9 23.423.9 25.3 25.8 26.1 27.0 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

FIG. 1 depicts an XRPD pattern of Form A of compound 1.

FIG. 2 depicts a DSC thermogram and TGA trace of Form A of compound 1.

FIG. 3 depicts a DVS plot of Form A of compound 1.

Form B of Compound 1

Form B of compound 1 was prepared as follows.

Procedure A: compound 1 was slurried in 10 volumes of methanol for 8hours at 20° C., filtered, and dried.

Procedure B: compound 1 was dissolved in MeOH/CH₂Cl₂ (11.20 mg/mL),dried under nitrogen purge, then slurried in MeOH overnight, filteredand dried in a vacuum oven at ambient temperature until analysis.

Characterization of the resulting material demonstrated a crystallineForm B.

Table 2, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form B of compound 1.

TABLE 2 XRPD Peak Positions for Form B of Compound 1 Position (°2 θ) 4.67.2 8.3 9.3 11.6 13.6 14.4 16.5 17.7 18.7 21.0 21.3 23.2 23.5 24.4 27.5¹ In this and all subsequent tables, the position 2 θ is within ±0.2.

FIG. 4 depicts an XRPD pattern of Form B of compound 1.

FIG. 5 depicts a DSC thermogram of Form B of compound 1.

FIG. 6 depicts a TGA trace of Form B of compound 1.

Elemental analysis—Calculated: C, 57.64; H, 4.62; N, 18.33; Found: C,57.46; H, 4.58; N, 18.36.

Karl Fisher titration: 0%

Form C of Compound 1

Form C of Compound 1 was prepared as follows.

Procedure A: Form A of compound 1 was slurried in methyl acetate,acetone, or tetrahydrofuran for seven days at room temperature.

Procedure B: 6.8 g of free base Form B were charged to 41 mLisopropylacetate and slurried at 20° C. for about 1 hour. The batch wasfiltered, washed with 7 mL of isopropyl acetate and dried under reducedpressure to yield 6.4 g.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form C.

Table 3, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form C of compound 1.

TABLE 3 XRPD Peak Positions for Form C of Compound 1 Position (°2 θ) 7.68.8 9.6 11.7 12.3 14.5 15.3 15.9 17.5 18.0 20.1 21.0 22.8 23.4 23.8 24.725.2 25.5 26.4 27.7 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

FIG. 7 depicts an XRPD pattern of Form C of compound 1.

FIG. 8 depicts a DSC thermogram of Form C of compound 1.

FIG. 9 depicts a TGA trace of Form C of compound 1.

Form D of Compound 1

Form D of compound 1 was prepared as follows.

Procedure: Form B of Compound 1 (400 mg) was charged to a vial with 1.7mL tetrahydrofuran and 0.3 mL water and vigorously stirred. After 24hours, the slurry was filtered and dried in a vacuum oven at 45° C.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form D.

Table 4, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form D of compound 1.

TABLE 4 XRPD Peak Positions for Form D of Compound 1 Position (°2 θ) 8.28.9 9.5 9.6 10.6 15.0 17.3 17.7 19.1 20.2 21.1 22.0 22.4 23.7 24.7 25.225.9 26.5 28.6 35.1 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

FIG. 10 depicts an XRPD pattern of Form D of compound 1.

FIG. 11 depicts a DSC thermogram of Form D of compound 1.

FIG. 12 depicts a TGA trace of Form D of compound 1.

Free Base Competitive Slurries:

Three competitive slurry experiments were performed:

1: Form A (20.0 mg)+Form C (20.4 mg) in 0.4 ml ethyl acetate

2: Form B (15.7 mg)+Form C (15.6 mg) in 0.3 ml ethyl acetate

3: Form A (13.3 mg)+Form B (11.5 mg) in 0.3 ml ethyl acetate

The three slurries were stirred vigorously for three days. Solids werethen filtered and dried. XRPD and DSC showed conversion to form C forall three experiments.

About 20 mg Form C was stirred in methanol (˜2 mL) at room temperaturefor 24 hours. Solids were filtered and dried. XRPD and DSC showed solidsconverted to Form B.

Form B of compound 1 was heated at 5° C./min in an XRD-DSC instrument.Both XRPD and DSC were recorded simultaneously, indicating Form Bexperienced solid-solid transition between 153° C. and 160° C.,resulting in Form A, which melted around 222° C. and recrystallized tobecome Form C, which melted around 235° C.

Example 2 Preparation of Forms A-D of Compound 2

Form A of Compound 2

Form A of compound 2 was prepared as follows.

Procedure A: Compound 1 was dissolved in 15× tetrahydrofuran. One molarequivalent of 2 molar phosphoric acid in acetonitrile was charged. Thebatch was slurried at 20° C. for 1 to 2 hours. The solvent was removedunder reduced pressure. The resulting solids were slurried in acetonefor about 16 hours at 20° C., filtered and dried.

Procedure B: Compound 1 was dissolved in THF. Equal molar equivalent of1.08 M phosphoric acid in acetonitrile was charged. The sample wasshaken at ambient temperature at 200 RPM for 1 hour. The solvent wasremoved under nitrogen purge. The resulting solids were slurried inacetone with a stirring bar at ambient temperature overnight, thenfiltered and dried in vacuum oven at 30° C. overnight.

Procedure C: Compound 1 was dissolved in THF (20×vol) at 20° C. Seeds ofcompound 2 Form A (5% wt) were charged. A 1 M solution of phosphoricacid (1 mol eq.) in ethanol was charged. The batch was left undervigorous agitation for two hours. Solvent exchange to isopropyl acetatewas carried out with a constant volume distillation under reducedpressure, with temperature not exceeding 40° C. The batch was cooled to20° C. The solvent was removed under nitrogen purge. The batch wasfiltered, washed two times with isopropyl acetate and dried in a vacuumoven at ˜40° C. overnight, under vacuum with nitrogen bleed.

Procedure D: Compound 1 was dissolved in 9×vol THF/H₂O (95:5 vol). Asolution of H₃PO₄ (1.2 mol eq.) in ethanol was charged to a secondflask, seeds of compound 2 form A (5%) were charged and vigorousagitation was started. The solution of compound 1 was charged to theH₃PO₄ solution (reverse addition) over one hour. The slurry was aged forone hour. Solvent exchange to ethanol was started (constant volumevacuum distillation with continuous addition of ethanol, final THF NMT0.5%). The batch was cooled to 20° C., filtered and dried in a vacuumoven at ˜40° C. overnight, under vacuum with nitrogen bleed.

Procedure E: Compound 1 was dissolved in 10×vol THF/H₂O (95:5 vol).Isopropyl alcohol (5×vol) was charged. Constant volume distillation,with continuous addition of isopropyl alcohol was started at atmosphericpressure. Solvent exchange was carried out until THF content was below5%. Compound 1 recrystallized during the solvent exchange. The batch wascooled to 30° C. A 1 M solution of H₃PO₄ in IPA was charged over 2hours. Seeds of compound 2 Form A (1%) were then charged. The batch wasstirred vigorously overnight. The batch was filtered and dried in avacuum oven at ˜40° C. overnight, under vacuum with nitrogen bleed.

Procedure F: Compound 1 was dissolved in 9×vol THF/H₂O (95:5 vol). Afterpolish filtration, distillation to reduce volume from 9× to 5× wasperformed, followed by addition of 8× ethyl acetate to bring the totalvolume to 13×. Solvent exchange to ethyl acetate, with constant volumedistillation was carried out (final THF NMT 2%). The temperature wasthen reduced to 30° C. Seeds of compound 2 (1% wt) were charged. Asolution of H₃PO₄ (1.2 eq.) in ethanol (5×) was then dosed in over 2hours. The temperature was reduced to 20° C., the batch was aged for 12hours under vigorous stirring, then filtered, washed two times withethyl acetate and dried in a vacuum oven at ˜40° C. overnight, undervacuum with nitrogen bleed.

Procedure G: Compound 1 was charged to a reactor, then ethanol (4×vol)and ethyl acetate (6×), were charged. The batch was agitated at 30° C. Asolution of H₃PO₄ (1.2 mol eq.) in ethanol (2×vol) was charged over 2hours. Seeds of compound 2 Form A (1%) were charged. The batch wasfiltered, washed two times with ethyl acetate, dried overnight at ˜40°C., under vacuum with nitrogen bleed.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 2. Up to 3.8% water uptake was observed forthis Form at 95% relative humidity.

Table 5, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form A of compound 2.

TABLE 5 XRPD Peak Positions for Form A of Compound 2 Position (°2 θ) 5.96.3 6.8 9.8 10.1 11.1 13.8 14.4 15.4 16.0 16.6 17.3 17.9 18.9 19.2 19.720.3 20.8 21.3 22.2 23.0 23.3 23.6 24.0 24.7 25.5 26.0 26.8 27.4 27.928.4 29.2 30.5 31.3 31.8 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

FIG. 13 depicts an XRPD pattern of Form A of compound 2.

FIG. 14 depicts a DSC thermogram of Form A of compound 2.

FIG. 15 depicts a TGA trace of Form A of compound 2.

FIG. 16 depicts a DVS plot of Form A of compound 2.

Elemental analysis—Calculated: C, 47.49; H, 4.35; N, 15.10; P, 5.57;Found: C, 47.09; H, 4.33; N, 14.90; P, 5.57.

Karl Fisher titration: 0.22%

Form B of Compound 2

Form B of compound 2 was prepared as follows.

Procedure: The phosphate salt of compound 1 was dissolved intetrahydrofuran or ethanol and filtered using a syringe filter. Thesolution was evaporated at room temperature under a nitrogen stream.

Characterization of the resulting material demonstrated a crystallineForm B of compound 2 in the form of a hydrate.

Table 6, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form B of compound 2.

TABLE 6 XRPD Peak Positions for Form B of Compound 2 Position (°2 θ) 3.67.3 8.6 9.5 10.7 12.0 13.5 14.6 15.0 15.7 16.6 18.2 19.2 19.9 20.3 21.622.0 22.5 22.9 23.4 24.1 24.9 25.3 25.7 26.3 26.9 27.8 28.7 29.5 30.231.8 34.2 36.1 37.1 38.8 39.3 ¹ In this and all subsequent tables, theposition 2 θ is within ±0.2.

FIG. 17 depicts an XRPD pattern of Form B of compound 2.

FIG. 18 depicts a DSC thermogram of Form B of compound 2.

FIG. 19 depicts a TGA trace of Form B of compound 2.

FIG. 20 depicts a DVS plot of Form B of compound 2.

Phosphate content: 17.8 wt %

Karl Fisher titration: 3.1%

Form C of Compound 2

Form C of compound 2 was prepared as follows.

Procedure: The phosphate salt of compound 1 was dissolved in ethanol atroom temperature and filtered using a syringe filter. Three to fivevolumes of acetonitrile was added as anti-solvent. The mixture wascooled in a refrigerator. Precipitated solids were isolated byfiltration and air dried.

Characterization of the resulting material demonstrated a crystallineForm C of compound 2.

Table 7, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form C of compound 2.

TABLE 7 XRPD Peak Positions for Form C of Compound 2 Position (°2 θ) 4.26.8 8.4 9.3 11.6 12.5 12.7 13.7 15.3 15.8 16.5 18.7 19.4 20.5 22.0 22.724.5 25.2 26.2 32.0 ¹ In this and all subsequent tables, the position 2θ is within ±0.2.

FIG. 21 depicts an XRPD pattern of Form C of compound 2.

FIG. 22 depicts a DSC thermogram of Form C of compound 2.

FIG. 23 depicts a TGA trace of Form C of compound 2.

FIG. 24 depicts a DVS plot of Form C of compound 2.

Phosphate content: 16.8 wt %

Karl Fisher titration: 0.14%

Form D of Compound 2

Form D of compound 2 was prepared as follows.

Procedure: The phosphate salt of compound 1 (i.e., compound 2, Form C)was heated to 140° C. to obtain Form D of compound 2. Alternatively,compound 1 free base (3 g) was dissolved in about 60 ml of THF.Phosphoric acid (1 molar equiv., 1M in water) was charged. The solutionwas stirred for one hour followed by removal of the solvent underreduced pressure. Acetone (10 volumes) was charged to the isolated solidand the slurry was agitated overnight after which the solids werecollected and dried under reduced pressure at about 40° C.

Characterization of the resulting material demonstrated a crystallineForm D of compound 2.

Table 8, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form D of compound 2.

TABLE 8 XRPD Peak Positions for Form D of Compound 2 Position (°2 θ) 7.18.1 9.1 10.4 10.6 11.2 12.9 13.9 15.8 16.4 17.2 17.7 18.7 19.0 20.2 20.721.0 22.1 22.7 24.5 25.1 26.4 27.4 27.8 28.7 29.1 31.0 31.5 33.8 36.337.0 38.0 ¹ In this and all subsequent tables, the position 2 θ iswithin ±0.2.

FIG. 25 depicts an XRPD pattern of Form D of compound 2.

FIG. 26 depicts a DSC thermogram of Form D of compound 2.

FIG. 27 depicts a TGA trace of Form D of compound 2.

Phosphate Interconversions

From polymorph screen:

Starting Temperature/ Form(s) Solvent/Condition Condition XRPD ResultForm B slurry in MeOH RT, 5 days free base (Form B) Form B slurry inEtOH RT, 5 days Form A + free base (Form C) Form B slurry in acetone RT,5 days Form A Form B slurry in MeCN RT, 5 days Form A Form B slurry inRT, 5 days free base (Form D) MeCN/water (1:1)

Example 3 Preparation of Form A of Compound 3

Form A of Compound 3

Form A of compound 3 was prepared as follows.

Procedure: Compound 1 was dissolved in 20 volumes of isopropanol. Eightmolar equivalents of phosphoric acid were charged. The reaction washeated to 60° C. for 24 hours, then cooled to 20° C., filtered, washedwith 10 volumes of isopropanol, and dried under reduced pressure at 40°C.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 3.

Table 9, supra, is reproduced below and sets forth the X-ray diffractionpeaks observed for Form A of compound 3.

TABLE 9 XRPD Peak Positions for Form A of Compound 3 Position (°2θ) 5.77.1 8.9 10.3 11.0 11.4 13.2 14.2 14.5 17.2 17.7 18.4 19.4 19.9 20.6 20.822.1 22.5 24.3 25.5 ¹In this and all subsequent tables, the position 2θis within ±0.2.

FIG. 28 depicts an XRPD pattern of Form A of compound 3.

FIG. 29 depicts a DSC thermogram of Form A of compound 3.

FIG. 30 depicts a TGA trace of Form A of compound 3.

FIG. 31 depicts a DVS plot of Form A of compound 3.

Elemental analysis—Calculated: C, 40.38; H, 4.16; N, 12.84; P, 9.47;Found: C, 40.01; H, 4.15; N, 12.61; P, 9.69.

Example 4 Preparation of Forms A-I of Compound 4

Form A of Compound 4

Form A of compound 4 was prepared as follows.

Procedure A: Two grams of the hydrochloride salt of compound 1 weredissolved in 10 mL of methanol and passed through a 0.2 uM filter. Thesolution was reduced in volume to about 3 mL and stirred for about 16hours at 23° C. The resulting solids were collected by suctionfiltration and dried under a nitrogen stream.

Procedure B: 507 mg of compound 1 were mixed with 8 mL of MeOH/CH₂Cl₂(1/1 v/v, premixed), followed by addition of 1.1 mL 1N HCl (indiethylether). The solution was stirred for 1 hour to become a clearsolution. The solution was dried in a fume hood under nitrogen purge.Next, 1 mL of methanol was added to the vial, which was vortex agitateduntil precipitation was observed. The vial was capped and stirred atroom temperature overnight. The solids were recovered through filtrationand dried in a vacuum oven at room temperature.

Characterization of the resulting material demonstrated a crystallineForm A of compound 4 in the form of a hydrate.

Table 10, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 4.

TABLE 10 XRPD Peak Positions for Form A of Compound 4 Position (°2θ) 7.59.3 11.2 11.9 14.2 15.0 15.3 15.7 21.4 21.9 22.6 22.8 23.4 24.6 24.825.2 26.4 26.8 30.5 34.1 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 32 depicts an XRPD pattern of Form A of compound 4.

FIG. 33 depicts a DSC thermogram of Form A of compound 4.

FIG. 34 depicts a TGA trace of Form A of compound 4.

FIG. 35 depicts a DVS plot of Form A of compound 4.

Elemental analysis—Calculated: C, 51.52; H, 4.72; Cl, 6.91; N, 16.38;Found: C, 51.89; H, 4.51; Cl, 7.11; N, 16.52.

Karl Fischer titration: 2.56%

Form B of Compound 4

Form B of compound 4 was prepared as follows.

Procedure: Compound 1 was dissolved in tetrahydrofuran. An equal molarequivalent of 1M HCl in diethyl ether was charged. The sample was shakenat ambient temperature at 200 RPM for 1 hour. The solvent was removedunder nitrogen purge. The resulting solids were slurried in acetonitrilewith a stirring bar at ambient temperature overnight, then filtered anddried in a vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystallineForm B of compound 4.

Table 11, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form B of compound 4.

TABLE 11 XRPD Peak Positions for Form B of Compound 4 Position (°2θ) 8.08.4 9.1 11.0 11.8 12.7 16.2 17.2 17.8 18.9 20.4 20.9 23.7 23.9 24.7 25.425.6 25.9 29.2 30.7 ¹In this and all subsequent tables, the position 2θis within ±0.2.

FIG. 36 depicts an XRPD pattern of Form B of compound 4.

FIG. 37 depicts a DSC thermogram and TGA trace of Form B of compound 4.

Form C of Compound 4

Form C of compound 4 was prepared as follows.

Procedure: Form B of compound 4 was slurried in acetone for 5 days atroom temperature.

Characterization of the resulting material demonstrated a crystallineForm C of compound 4.

Table 12, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form C of compound 4.

TABLE 12 XRPD Peak Positions for Form C of Compound 4 Position (°2θ) 7.78.2 9.0 9.5 10.2 12.1 12.4 12.6 13.5 15.3 16.4 18.4 21.0 21.3 23.1 23.423.7 24.2 25.5 25.7 ¹In this and all subsequent tables, the position 2θis within ±0.2.

FIG. 38 depicts an XRPD pattern of Form C of compound 4.

FIG. 39 depicts a DSC thermogram of Form C of compound 4.

Form D of Compound 4

Form D of compound 4 was prepared as follows.

Procedure: Compound 1 (3 g, 6.5 mmol) was charged to a 150 mL roundbottom flask. Methanol (15×) was charged. A solution of HCl (3.27 mL,6.54 mmol; 2M in diethyl ether) was charged to the flask. The solidscompletely dissolved. The solution was stirred overnight, thentransferred to a crystallizing dish for slow evaporation of the solvent.Solids were then placed to dry in a vacuum oven with a nitrogen bleed at40° C.

Characterization of the resulting material demonstrated a crystallineForm D of compound 4.

Table 13, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form D of compound 4.

TABLE 13 XRPD Peak Positions for Form D of Compound 4 Position (°2θ) 7.19.1 11.2 12.7 14.0 14.4 14.6 17.0 17.2 21.7 22.0 22.4 22.8 23.7 24.825.3 25.5 28.0 34.2 35.7 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 40 depicts an XRPD pattern of Form D of compound 4.

FIG. 41 depicts a DSC thermogram of Form D of compound 4.

FIG. 42 depicts a DSC thermogram and TGA trace of Form D of compound 4.

FIG. 43 depicts a DVS plot of Form D of compound 4.

Karl Fischer titration: 1.21%

Form E of Compound 4

Form E of compound 4 was prepared as follows.

Procedure: Form B of compound 4 was slurried in acetonitrile/water (1:1)for five days at room temperature.

Characterization of the resulting material demonstrated a crystallineForm E of compound 4.

Table 14, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form E of compound 4.

TABLE 14 XRPD Peak Positions for Form E of Compound 4 Position (°2θ) 7.79.0 10.7 14.4 15.5 17.1 18.2 19.8 20.4 21.5 23.1 24.4 24.6 25.0 27.027.3 28.1 30.9 31.2 37.6 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 44 depicts an XRPD pattern of Form E of compound 4.

FIG. 45 depicts a DSC thermogram of Form E of compound 4.

Form F of Compound 4

Form F of compound 4 was prepared as follows.

Procedure: Form B of compound 4 was slurried in isopropanol for fivedays at room temperature.

Characterization of the resulting material demonstrated a crystallineForm F of compound 4.

Table 15, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form F of compound 4.

TABLE 15 XRPD Peak Positions for Form F of Compound 4 Position (°2θ) 6.17.7 11.3 12.4 13.8 15.4 16.9 17.7 18.6 19.5 22.6 22.9 23.1 23.6 24.925.7 26.1 30.2 34.2 35.0 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 46 depicts an XRPD pattern of Form F of compound 4.

FIG. 47 depicts a DSC thermogram of Form F of compound 4.

Form G of Compound 4

Form G of compound 4 was prepared as follows.

Procedure: Form B of compound 4 was slurried in acetonitrile for fivedays at room temperature.

Characterization of the resulting material demonstrated a crystallineForm G of compound 4.

Table 16, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form G of compound 4.

TABLE 16 XRPD Peak Positions for Form G of Compound 4 Position (°2θ) 5.28.5 8.7 10.5 14.8 15.6 19.0 19.5 20.7 21.0 21.9 22.2 23.3 25.7 27.0 27.429.6 30.7 31.3 ¹In this and all subsequent tables, the position 2θ iswithin ±0.2.

FIG. 48 depicts an XRPD pattern of Form G of compound 4.

FIG. 49 depicts a DSC thermogram of Form G of compound 4.

Form H of Compound 4

Form H of compound 4 was prepared as follows.

Procedure: 1 g of the HCl salt of compound 1 was dissolved in methanol(4 mL) and filtered through a syringe filter. The solvent was evaporatedslowly under a stream of nitrogen until the reaction mixture wasslightly cloudy. The salt solution was stirred at room temperatureovernight, filtered, and dried at room temperature under a stream ofnitrogen for 15 minutes.

Characterization of the resulting material demonstrated a crystallineForm H of compound 4.

Table 17, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form H of compound 4.

TABLE 17 XRPD Peak Positions for Form H of Compound 4 Position (°2θ) 7.28.5 9.1 10.2 13.1 14.5 15.8 18.1 18.8 20.5 21.0 21.7 22.5 23.3 24.2 24.625.3 25.8 28.8 29.9 ¹In this and all subsequent tables, the position 2θis within ±0.2.

FIG. 50 depicts an XRPD pattern of Form H of compound 4.

FIG. 51 depicts a DSC thermogram of Form H of compound 4.

Form I of Compound 4

Form I of Compound 4 was prepared as follows.

Procedure: Form H of compound 4 was slurried in water for two hours atroom temperature.

Characterization of the resulting material demonstrated a crystallineForm I of compound 4.

Table 18, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form I of compound 4.

TABLE 18 XRPD Peak Positions for Form I of Compound 4 Position (°2θ) 4.77.1 9.3 10.8 11.9 14.1 15.0 16.7 18.8 20.3 21.1 22.2 23.1 23.5 24.2 25.426.0 29.1 ¹In this and all subsequent tables, the position 2θ is within±0.2.

FIG. 52 depicts an XRPD pattern of Form I of compound 4.

Example 5 Preparation of Forms A-E of Compound 5

Form A of Compound 5

Form A of compound 5 was prepared as follows.

Procedure A: 4.1 g of compound 1 was dissolved in tetrahydrofuran (15×).Hydrobromic acid (1 molar equivalent of 48% HBr diluted to 2M inacetonitrile) was charged and agitated for 2 hours at 20° C. The solventwas removed under reduced pressure and the resulting solids wereslurried in acetone for 16 hours at 20° C., filtered and dried to yield4.89 g product.

Procedure B: Compound 1 was dissolved in tetrahydrofuran. Equal molarequivalent of 8.84 M HBr in water was charged. The sample was shaken atambient temperature at 200 RPM for 1 hour. The solvent was removed undernitrogen purge. The resulting solids were slurried in acetonitrile (oracetone) with a stirring bar at ambient temperature overnight, thenfiltered and dried in vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 5.

Table 19, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 5.

TABLE 19 XRPD Peak Positions for Form A of Compound 5 Position (°2θ) 7.59.5 11.3 13.0 14.3 14.7 15.0 15.7 17.3 20.3 20.9 21.6 22.6 23.2 23.724.8 26.0 28.8 30.5 33.8 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 53 depicts an XRPD pattern of Form A of compound 5.

FIG. 54 depicts a DSC thermogram of Form A of compound 5.

FIG. 55 depicts a TGA trace of Form A of compound 5.

FIG. 56 depicts a DVS plot of Form A of compound 5.

Elemental analysis—Calculated: C, 48.99; H, 4.11; Br, 14.81; N, 15.58;Found: C, 48.37; H, 4.19; Br, 15.34; N, 15.28.

Karl Fischer titration: 0.35%

Form B of Compound 5

Form B of compound 5 was prepared as follows.

Procedure: Compound 1 was dissolved in tetrahydrofuran. Equal molarequivalent of 8.84 M HBr in water was charged. The sample was shaken atambient temperature at 200 RPM for 1 hour. The solvent was removed undernitrogen purge. The resulting solids were slurried in methyl ethylketone or toluene with magnetic stirring at ambient temperatureovernight, then filtered and dried in a vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystallineForm B of compound 5.

Table 20, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form B of compound 5.

TABLE 20 XRPD Peak Positions for Form B of Compound 5 Position (°2θ) 8.311.8 12.3 14.2 16.2 17.9 18.7 18.9 20.3 20.5 20.8 21.1 23.8 24.5 25.525.7 26.3 29.2 30.7 31.9 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 57 depicts an XRPD pattern of Form B of compound 5.

FIG. 58 depicts a DSC thermogram and TGA trace of Form B of compound 5.

Form C of Compound 5

Form C of compound 5 was prepared as follows.

Procedure: Compound 1 (0.5 g, 1.091 mmol) was dissolved in THF (5 ml,61.0 mmol) at room temperature. HBr (0.148 ml, 1.309 mmol) was added tosolution to form a slightly hazy solution, which was stirred at roomtemperature for 15 min. Next was added acetonitrile (5 mL). Nitrogen wasstreamed over the hazy solution until solvent was fully evaporated. Paleyellow solid formed. The product was charged with acetonitrile (5 mL),slurried overnight, filtered, and dried.

Characterization of the resulting material demonstrated a crystallineForm C of compound 5.

Table 21, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form C of compound 5.

TABLE 21 XRPD Peak Positions for Form C of Compound 5 Position (°2θ)7.46x 8.4 10.5 15.4 15.8 17.4 20.1 20.8 22.1 22.3 22.6 23.2 24.2 24.525.9 26.6 29.0 31.8 33.8 37.7 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 59 depicts an XRPD pattern of Form C of compound 5.

FIG. 60 depicts a DSC thermogram and TGA trace of Form C of compound 5.

Form D of Compound 5

Form D of compound 5 was prepared as follows.

Procedure: Compound 1 (3.0 g, 6.54 mmol) was dissolved in 60 mLtetrahydrofuran. HBr (48% diluted to 1M with water) was charged in a 1:1ratio. The solution was stirred for one hour after which the solvent wasevaporated under reduced pressure. Acetonitrile (10×) was charged andthe slurry was vigorously stirred overnight. Solids were filtered anddried in a vacuum oven at 40° C. with a nitrogen bleed.

Characterization of the resulting material demonstrated a crystallineForm D of compound 5.

Table 22, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form D of compound 5.

TABLE 22 XRPD Peak Positions for Form D of Compound 5 Position (°2θ) 7.29.4 10.8 11.8 15.1 16.9 18.9 20.4 21.6 22.3 23.7 24.3 24.7 25.5 26.129.0 30.3 30.6 32.1 35.2 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 61 depicts an XRPD pattern of Form D of compound 5.

FIG. 62 depicts a DSC thermogram and TGA trace of Form D of compound 5.

Form E of Compound 5

Form E of compound 5 was prepared as follows.

Procedure: Compound 1 (3 g, 6.54 mmol) was dissolved in ˜60 mltetrahydrofuran. HBr (48% diluted to ˜1M with water) was charged in a1:1 ratio. The solution was stirred for one hour, after which thesolvent was evaporated under reduced pressure. Acetonitrile (10×) wascharged and the slurry was vigorously stirred overnight. The solvent wasremoved under reduced pressure. Tetrahydrofuran (20×) was charged. Theslurry was vigorously stirred, then the tetrahydrofuran was removedunder reduced pressure to facilitate the removal of water. Acetonitrile(10×) was charged and the slurry was again vigorously stirred overnight.Solids were filtered and dried in a vacuum oven at 40° C., with nitrogenbleed.

Characterization of the resulting material demonstrated a crystallineForm E of compound 5.

Table 23, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form E of compound 5.

TABLE 23 XRPD Peak Positions for Form E of Compound 5 Position (°2θ) 7.88.7 10.0 11.6 15.0 16.4 17.5 18.7 21.5 22.8 23.8 24.3 25.2 25.8 28.829.1 30.3 31.7 33.7 36.8 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 63 depicts an XRPD pattern of Form E of compound 5.

FIG. 64 depicts a DSC thermogram of Form E of compound 5.

FIG. 65 depicts a DVS plot of Form E of compound 5.

Example 6 Preparation of Forms A-C of Compound 6

Form A of Compound 6

Form A of compound 6 was prepared as follows.

Procedure A: Compound 1 (4.1 g, 8.94 mmol) was dissolved in 15×tetrahydrofuran. One molar equivalent of 2 M sulfuric acid inacetonitrile was charged. Solids precipitated as the acid was charged.The slurry was stirred for 2 hours at 20° C., then the solvent wasremoved under reduced pressure. The resulting solids were slurried inethyl acetate at 20° C. for about 16 hours, filtered, and dried.

Procedure B: Compound 1 was dissolved in tetrahydrofuran. Equal molarequivalent of 1.18 M H₂SO₄ in acetonitrile was charged. The sample wasshaken at ambient temperature at 200 RPM for 1 hour. The solvent wasremoved under nitrogen purge. The resulting solids were slurried inethyl acetate with a stirring bar at ambient temperature overnight, thenfiltered and dried in vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 6.

Table 24, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 6.

TABLE 24 XRPD Peak Positions for Form A of Compound 6 Position (° 2θ)6.2 7.1 9.9 14.2 14.7 19.4 19.5 20.1 20.2 20.7 21.4 23.4 23.9 24.3 24.825.3 26.0 26.9 28.7 29.8 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 66 depicts an XRPD pattern of Form A of compound 6.

FIG. 67 depicts a DSC thermogram of Form A of compound 6.

FIG. 68 depicts a TGA trace of Form A of compound 6.

FIG. 69 depicts a DVS plot of Form A of compound 6.

Elemental analysis—Calculated: C, 47.48; H, 4.17; N, 15.10; S, 5.76;Found: C, 46.89; H, 4.31; N, 14.73; S, 6.05.

Karl Fischer titration: 0.69%

Form B of Compound 6

Form B of compound 6 was prepared as follows.

Procedure A: Compound 1 (3 g, 6.54 mmol) was dissolved in ˜60 mltetrahydrofuran. H₂SO₄ (95% diluted to ˜1M with water) was charged. Thesolution was stirred for more than one hour, after which the solvent wasremoved under reduced pressure. Ethyl acetate (10×) was charged. Theslurry was vigorously stirred overnight, after which the solids werefiltered and dried in a vacuum oven at 40° C. with nitrogen bleed.

Procedure B: Compound 1 was dissolved in tetrahydrofuran. Equal molarequivalent of 1.18 M H₂SO₄ in acetonitrile was charged. The sample wasshaken at ambient temperature at 200 RPM for 1 hour. The solvent wasremoved under nitrogen purge. The resulting solids were slurried inacetone with a stirring bar at ambient temperature overnight, thenfiltered and dried in vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystallineForm B of compound 6.

Table 25, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form B of compound 6.

TABLE 25 XRPD Peak Positions for Form B of Compound 6 Position (° 2θ)7.1 7.6 10.1 11.4 11.6 12.4 13.7 15.2 17.3 17.8 18.7 18.7 20.3 21.7 22.924.1 25.4 26.0 29.7 34.7 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 70 depicts an XRPD pattern of Form B of compound 6.

FIG. 71 depicts a DSC thermogram and TGA trace of Form B of compound 6.

Form C of Compound 6

Form C of compound 6 was prepared as follows.

Procedure: Compound 1 (3 g, 6.54 mmol) was dissolved in tetrahydrofuran.Equimolar equivalent of 1.18 M H₂SO₄ in acetonitrile was charged. Thesample was shaken at ambient temperature at 200 RPM for 1 hour. Thesolvent was removed under nitrogen purge. The resulting solids wereslurried in methanol with a stirring bar at ambient temperatureovernight, after which the solids were filtered and dried in a vacuumoven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystallineForm C of compound 6.

Table 26, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form C of compound 6.

TABLE 26 XRPD Peak Positions for Form C of Compound 6 Position (° 2θ)7.1 7.6 8.3 9.3 12.6 13.5 14.2 17.4 18.1 19.6 20.2 20.5 20.9 21.2 23.124.4 25.1 26.2 27.9 29.9 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 72 depicts an XRPD pattern of Form C of compound 6.

FIG. 73 depicts a DSC thermogram and TGA trace of Form C of compound 6.

Example 7 Preparation of Form A of Compound 7

Form A of Compound 7

Form A of compound 7 was prepared as follows.

Procedure: 0.22 g of 98% sulphuric acid was diluted in 10 mLacetonitrile. 0.5 g of compound 1 was charged to the sulphuric acidsolution and agitated at 22° C. for 2 hours. The solids were filtered,washed three times, each with 2 mL acetonitrile, and dried under reducedpressure at 40° C. to yield 0.61 g of the bis-sulfate salt.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 7.

Table 27, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 7.

TABLE 27 XRPD Peak Positions for Form A of Compound 7 Position (° 2θ)7.3 8.7 9.6 11.4 11.5 14.1 17.9 18.2 19.0 19.2 20.5 20.7 21.0 22.2 23.524.3 24.3 27.5 28.6 31.1 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 74 depicts an XRPD pattern of Form A of compound 7.

FIG. 75 depicts a DSC thermogram and TGA trace of Form A of compound 7.

FIG. 76 depicts a DVS plot of Form A of compound 7.

Elemental analysis—Calculated: C, 40.37; H, 3.85; N, 12.84; S, 9.80;Found: C, 40.27; H, 3.92; N, 12.69; S, 9.63.

Example 8 Preparation of Forms A-D of Compound 8

Form A of Compound 8

Form A of compound 8 was prepared as follows.

Procedure: Compound 1 was dissolved in tetrahydrofuran. An equal molarequivalent of 1.3 M p-toluenesulfonic acid monohydrate in methanol wascharged. The sample was shaken at ambient temperature at 200 RPM for 1hour. The solvent was removed under nitrogen purge. The resulting solidswere slurried in acetonitrile with a stir bar at ambient temperatureovernight, then filtered and dried in a vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystallineForm A of compound 8.

Table 28, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 8.

TABLE 28 XRPD Peak Positions for Form A of Compound 8 Position (° 2θ)8.6 9.0 12.4 12.8 13.4 16.1 16.4 16.6 17.0 17.9 19.1 20.0 20.5 22.9 23.523.7 23.8 24.8 27.8 30.7 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 77 depicts an XRPD pattern of Form A of compound 8.

FIG. 78 depicts a DSC thermogram and TGA trace of Form A of compound 8.

Form B of Compound 8

Form B of compound 8 was prepared as follows.

Procedure: Compound 1 was dissolved in tetrahydrofuran. An equal molarequivalent of 1.3 M p-toluenesulfonic acid monohydrate in methanol wascharged. The sample was shaken at ambient temperature at 200 RPM for 1hour. The solvent was removed under nitrogen purge. The resulting solidswere slurried in acetone with a stir bar at ambient temperatureovernight, then filtered and dried in a vacuum oven at 30° C. overnight.

Characterization of the resulting material demonstrated a crystallineForm B of compound 8.

Table 29, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form B of compound 8.

TABLE 29 XRPD Peak Positions for Form B of Compound 8 Position (° 2θ)8.6 8.9 12.2 16.2 16.5 16.9 17.2 17.9 19.0 19.1 20.1 23.1 23.4 23.6 24.624.7 25.1 26.3 27.6 28.2 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 79 depicts an XRPD pattern of Form B of compound 8.

FIG. 80 depicts a DSC thermogram and TGA trace of Form B of compound 8.

Form C of Compound 8

Form C of compound 8 was prepared as follows.

Procedure: Compound 1 was dissolved in tetrahydrofuran. An equal molarequivalent of 1.3 M p-toluenesulfonic acid monohydrate in methanol wascharged. The sample was shaken at ambient temperature at 200 RPM for 1hour. The solvent was removed under nitrogen purge. The resulting solidswere slurried in methylethyl ketone with a stir bar at ambienttemperature overnight, then filtered and dried in a vacuum oven at 30°C. overnight.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form C of compound 8.

Table 30, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form C of compound 8.

TABLE 30 XRPD Peak Positions for Form C of Compound 8 Peak No. Position(° 2θ) 8.8 23.1 9.5 23.8 12.5 24.2 13.3 24.6 14.2 25.2 16.9 26.3 17.430.3 17.8 31.1 18.9 31.8 20.1 38.0 ¹In this and all subsequent tables,the position 2θ is within ±0.2.

FIG. 81 depicts an XRPD pattern of Form C of compound 8.

FIG. 82 depicts a DSC thermogram and TGA trace of Form C of compound 8.

FIG. 83 depicts a DVS plot of Form C of compound 8.

Elemental analysis—Calculated: C, 55.23; H, 4.64; N, 13.33; S, 5.08;Found: C, 54.78; H, 4.58; N, 13.18; S, 5.35.

Form D of Compound 8

Form D of compound 8 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).An equal molar equivalent of 0.31 M p-toluenesulfonic acid monohydratein methanol was charged. The sample was shaken at ambient temperature at200 RPM for 1 hour. The solvent was removed under nitrogen purge. Theresulting solids were slurried in methanol at ambient temperatureovernight. No solids were obtained. The solution was dried undernitrogen purge, then was added methyl tert-butyl ether, and the solutionwas slurried overnight. No solids were obtained. The solution was thendried, hexane was added, and the solution was slurried overnight, thendried in a vacuum oven.

Characterization of the resulting material demonstrated an amorphousForm D of compound 8.

FIG. 84 depicts a DSC thermogram and TGA trace of Form D of compound 8.

Example 9 Preparation of Forms A-B of Compound 9

Form A of Compound 9

Form A of compound 9 was prepared as follows.

Procedure: Compound 1 was dissolved in tetrahydrofuran. An equal molarequivalent of 1.25 M benzenesulfonic acid in methanol was charged. Thesample was shaken at ambient temperature at 200 RPM for 1 hour. Thesolvent was removed under nitrogen purge. The resulting solids wereslurried in methyl ethyl ketone (or acetone) with a stir bar at ambienttemperature overnight, then filtered and dried in vacuum oven at 30° C.overnight.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 9.

Table 31, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 9.

TABLE 31 XRPD Peak Positions for Form A of Compound 9 Peak No. Position(° 2θ) 8.9 23.6 12.5 24.0 13.2 25.2 15.6 25.5 17.6 26.1 18.0 27.0 18.527.9 19.1 29.6 20.6 30.3 21.7 39.5 ¹In this and all subsequent tables,the position 2θ is within ±0.2.

FIG. 85 depicts an XRPD pattern of Form A of compound 9.

FIG. 86 depicts a DSC thermogram and TGA trace of Form A of compound 9.

FIG. 87 depicts a DVS plot of Form A of compound 9.

Elemental analysis—Calculated: C, 54.54; H, 4.41; N, 13.63; S, 5.20;Found: C, 54.20; H, 4.38; N, 13.60; S, 5.59.

Form B of Compound 9

Form B of compound 9 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).Equal molar equivalent of 0.14 M benzenesulfonic acid in methanol wascharged. The sample was shaken at ambient temperature at 200 RPM for 1hour. The solvent was removed under nitrogen purge. The resulting solidswere slurried in methanol at ambient temperature overnight, no solidswere obtained. So it was dried under nitrogen purge, then added withmethyl tert-butyl ether and slurried overnight, then dried in a vacuumoven.

Characterization of the resulting material demonstrated an amorphousForm B of compound 9.

FIG. 88 depicts a DSC thermogram and TGA trace of Form B of compound 9.

Example 10 Preparation of Forms A-B of Compound 10

Form A of Compound 10

Form A of compound 10 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).An equal molar equivalent of 0.31 M methanesulfonic acid in acetonitrilewas charged. The sample was shaken at ambient temperature at 200 RPM for1 hour. The solvent was removed under nitrogen purge. The resultingsolids were slurried in methanol at ambient temperature overnight, nosolids were obtained. The material was dried under nitrogen purge,followed by the addition of methyl tert-butyl ether, overnight slurry,filtration and drying in a vacuum oven.

Characterization of the resulting material demonstrated an amorphousForm A of compound 10.

FIG. 89 depicts a DSC thermogram and TGA trace of Form A of compound 10.

Form B of Compound 10

Form B of compound 10 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).An equal molar equivalent of 0.31 M methanesulfonic acid in acetonitrilewas charged. The sample was shaken at ambient temperature at 200 RPM for1 hour. The solvent was removed under nitrogen purge. Acetonitrile/water(1/1 v/v) was charged and slurried overnight, no solids were obtained.It was dried and slurried in hexane overnight and then dried in vacuumoven.

Characterization of the resulting material demonstrated a partiallycrystalline Form B of compound 10.

Table 32, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form B of compound 10.

TABLE 32 XRPD Peak Positions for Form B of Compound 10 Position (° 2θ)6.1 7.9 8.3 16.3 22.6 ¹In this and all subsequent tables, the position2θ is within ±0.2.

FIG. 90 depicts an XRPD pattern of Form B of compound 10.

FIG. 91 depicts a DSC thermogram and TGA trace of Form B of compound 10.

Example 11 Preparation of Form A of Compound 11

Form A of Compound 11

Form A of compound 11 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).Equal molar equivalent of 0.25 M maleic acid in methanol was charged.The sample was shaken at ambient temperature at 200 RPM for 1 hour. Thesolvent was removed under nitrogen purge. The resulting solids wereslurried in ethyl acetate at ambient temperature overnight, thenfiltered and dried in vacuum oven at ambient temperature.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 11.

Table 33, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 11.

TABLE 33 XRPD Peak Positions for Form A of Compound 11 Position (° 2θ)5.2 8.9 9.2 10.4 12.0 13.3 13.4 15.3 16.1 18.7 20.9 23.0 23.2 23.9 24.625.6 26.1 26.3 26.7 27.0 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 92 depicts an XRPD pattern of Form A of compound 11.

FIG. 93 depicts a DSC thermogram and TGA trace of Form A of compound 11.

Elemental analysis—Calculated: C, 54.54; H, 4.41; N, 13.63; S, 5.20;Found: C, 54.20; H, 4.38; N, 13.60; S, 5.59.

Example 12 Preparation of Forms A-C of Compound 12

Form A of Compound 12

Form A of compound 12 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).Equal molar equivalent of 0.15 M oxalic acid in methanol was charged.The sample was shaken at ambient temperature at 200 RPM for 1 hour. Thesolvent was removed under nitrogen purge. The resulting solids wereslurried in acetonitrile at ambient temperature overnight, then filteredand dried in vacuum oven at ambient temperature.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form A of compound 12.

Table 34, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form A of compound 12.

TABLE 34 XRPD Peak Positions for Form A of Compound 12 Position (° 2θ)5.4 5.8 6.8 9.7 10.3 12.3 13.4 14.4 16.4 17.4 17.7 20.3 22.0 23.4 23.724.9 25.2 26.9 30.2 35.4 ¹ In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 94 depicts an XRPD pattern of Form A of compound 12.

FIG. 95 depicts a DSC thermogram and TGA trace of Form A of compound 12.

Form B of Compound 12

Form B of compound 12 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).Equal molar equivalent of 0.15 M oxalic acid in MeOH was charged. Thesample was shaken at ambient temperature at 200 RPM for 1 hour. Thesolvent was removed under nitrogen purge. The resulting solids wereslurried in acetone at ambient temperature overnight, then filtered anddried in vacuum oven at ambient temperature.

Characterization of the resulting material demonstrated a crystallineForm B of compound 12.

Table 35, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form B of compound 12.

TABLE 35 XRPD Peak Positions for Form B of Compound 12 Position (° 2θ)5.0 5.8 8.3 9.1 9.9 12.5 13.4 14.8 15.2 16.7 17.4 20.3 21.7 24.8 25.326.3 26.8 28.1 29.2 30.6 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 96 depicts an XRPD pattern of Form B of compound 12.

FIG. 97 depicts a DSC thermogram and TGA trace of Form B of compound 12.

Form C of Compound 12

Form C of compound 12 was prepared as follows.

Procedure: Compound 1 was dissolved in MeOH/CH₂Cl₂ (1/1 v/v, pre-mixed).Equal molar equivalent of 0.15 M oxalic acid in methanol was charged.The sample was shaken at ambient temperature at 200 RPM for 1 hour. Thesolvent was removed under nitrogen purge. The resulting solids wereslurried in ethyl acetate at ambient temperature overnight, thenfiltered and dried in vacuum oven at ambient temperature.

Characterization of the resulting material demonstrated a crystalline,anhydrous Form C of compound 12.

Table 36, supra, is reproduced below and sets forth the X-raydiffraction peaks observed for Form C of compound 12.

TABLE 36 XRPD Peak Positions for Form C of Compound 12 Position (° 2θ)5.6 5.8 8.4 9.3 10.1 12.4 13.4 14.9 16.2 16.6 17.5 18.5 21.8 22.2 23.425.2 25.9 26.3 26.9 36.5 ¹In this and all subsequent tables, theposition 2θ is within ±0.2.

FIG. 98 depicts an XRPD pattern of Form C of compound 12.

FIG. 99 depicts a DSC thermogram and TGA trace of Form C of compound 12.

Example 13 Solubility in Water at Ambient Temperature

Each of compounds 1 through 9 were weighed into separate 8 mL clearglass vials. After addition of 3.2 mL of water, the vials were cappedand shaken on an orbital shaker at 300 RPM at ambient temperature for 24hours. The samples were removed from the shaker and the pH of each wasmeasured using a calibrated pH meter. Next, a portion of the each samplewas withdrawn and filtered using a PVDF-membrane syringe filter. Thefiltrate was analyzed using HPLC/UV with appropriate dilution. Thesolubility was reported as free base-equivalent value because the freebase was used as the standard for HPLC analysis. The rest of the sampleswere shaken for another 24 hours for 48-hour solubility measurementusing the same procedure. After the 48-hour solubility tests were run,the solid residues were recovered through filtration using 0.2 μmNylon-membrane centrifuge tube filters at 14000 RPM for 5 min andanalyzed using XRPD.

For the bis-phosphate complex and bis-sulfate salt, measurements wereonly performed at the 24-hour time point. The results are shown in Table37, below.

TABLE 37 Solubility in Water at Ambient Temperature Conc. (μg/mL) Conc.(μg/mL) Sample at 24 hours at 48 hours pH at 48 hrs Compound 1 0.07 0.056.33 (free base) Compound 2 19.40 91.69 2.48 (phosphate salt) Compound 3113 Not Not (bis-phosphate Determined Determined complex) Compound 4162.33 134.08 2.29 (HCl salt) Compound 5 190.63 207.42 2.27 (HBr salt)Compound 6 560.02 409.83 1.98 (sulfate salt) Compound 7 1170 Not Not(bis-sulfate salt) Determined Determined Compound 8 218.34 184.83 2.00(tosylate salt) Compound 9 173.63 143.49 2.10 (besylate salt)

Example 14 A Single Oral Dose Pharmacokinetic (PK) Study in Dogs withVarious Salt and Free Base Forms of Compound 1

The pharmacokinetics of compound 1 (free base, administered to dosinggroup 1), compound 2 (phosphate salt, administered to dosing group 4),compound 4 (hydrochloride salt, administered to dosing group 2),compound 5 (bromide salt, administered to dosing group 5), and compound6 (sulfate salt, administered to dosing group 3) were evaluated in dogs(2/sex/group) in a parallel design study. In addition, the effect offood on the systemic exposure to compounds 1, 2, 4, 5 and 6 was alsoevaluated. Compounds 1, 2, 4, 5 and 6 were orally administered at 15mg/kg to dogs in a fasted state (overnight fast) on day 1 andadministered under fed conditions (a meal was provided one hour prior todosing) on day 9. Doses were administered as a suspension in 5%Captisol/0.2% Tween 80/0.05M Citrate buffer (compound 1) and 5%Captisol/0.2% Tween (compounds 2, 4, 5 and 6). Animals were habituated(days 2 to 8) to consume their entire daily ration (˜400 g) in 1 hour.Pharmacokinetic samples were collected on days 1 and 9 at 0, 0.5, 1, 2,4, 6, 8, 12, and 24 hours after dosing. The summary of pharmacokineticparameters are shown in Table 38 below.

TABLE 38 Mean (SD) Pharmacokinetic Parameters in Dogs Day 1 (Fasted) Day9 (Fed) C_(max) AUC_(last) C_(max) AUC_(last) Salt Type ng/mL (ng ·h/mL) ng/mL (ng · h/mL) Compound 1,   98.1 286 293 1890 Form C   (51.9)(162) (112)  (980) Compound 4, 323 856 818 3350 Form A (135) (285) (47) (839) Compound 2, 345 1080  790 3880 Form A  (78) (511) (218) (1250)Compound 6, 364 1120  740 5590 Form A (204) (597) (433) (2480) Compound5, 393 1680  826 5030 Form A (171) (1210)  (211) (1020) Number ofanimals used were 2/sex/group

Compounds 2, 4, 5 and 6 demonstrated enhanced oral bioavailability indogs when compared to Compound 1 under both fasted and fed conditionswith their mean systemic exposure (AUC_(last)) to Compound 1 increasingby approximately either 3- to 6-fold (fasted; see FIG. 100(a)) or 2- to3-fold (fed; see FIG. 100(b)).

In dogs, a positive food effect was observed with both free base(Compound 1) and salt forms (Compounds 2, 4, 5 and 6). Systemic exposureincreased by approximately 3- to 7-fold under fed conditions as comparedto fasted conditions.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1.


2. The compound according to claim 1, wherein said compound iscrystalline.
 3. The compound according to claim 1, wherein said compoundis a crystalline solid substantially free of amorphous compound
 2. 4.The compound according to claim 1, wherein said compound issubstantially free of impurities.
 5. The compound according to claim 1,having one or more peaks in its XRPD selected from those at about 6.8,about 10.1, and about 20.8 degrees 2-theta.
 6. The compound according toclaim 5, having at least two peaks in its XRPD selected from those atabout 6.8, about 10.1, and about 20.8 degrees 2-theta.
 7. The compoundaccording to claim 6, wherein said compound is of Form A.
 8. Thecompound according to claim 1, having an XRPD substantially similar tothat depicted in FIG.
 13. 9. The compound according to claim 1, havingone or more peaks in its XRPD selected from those at about 3.6, about7.3, and about 15.0 degrees 2-theta.
 10. The compound according to claim9, having at least two peaks in its XRPD selected from those at about3.6, about 7.3, and about 15.0 degrees 2-theta.
 11. The compoundaccording to claim 10, wherein said compound is of Form B.
 12. Thecompound according to claim 1, having an XRPD substantially similar tothat depicted in FIG.
 17. 13. The compound according to claim 1, havingone or more peaks in its XRPD selected from those at about 8.4, about9.3, and about 16.5 degrees 2-theta.
 14. The compound according to claim13, having at least two peaks in its XRPD selected from those at about8.4, about 9.3, and about 16.5 degrees 2-theta.
 15. The compoundaccording to claim 14, wherein said compound is of Form C.
 16. Thecompound according to claim 1, having an XRPD substantially similar tothat depicted in FIG.
 21. 17. The compound according to claim 1, havingone or more peaks in its XRPD selected from those at about 9.1, about10.4, and about 25.1 degrees 2-theta.
 18. The compound according toclaim 17, having at least two peaks in its XRPD selected from those atabout 9.1, about 10.4, and about 25.1 degrees 2-theta.
 19. The compoundaccording to claim 18, wherein said compound is of Form D.
 20. Thecompound according to claim 1, having an XRPD substantially similar tothat depicted in FIG.
 25. 21. A composition comprising the compoundaccording to claim 1 and a pharmaceutically acceptable carrier orexcipient.
 22. A method of inhibiting one or both of ERK1 and ERK2 in apatient comprising administering to said patient a compound according toclaim 1 or composition thereof.
 23. A method of treating an ERK1- orERK2-mediated disorder in a patient, comprising administering to saidpatient a compound according to claim 1, or composition thereof.
 24. Themethod according to claim 23, wherein the disorder is selected fromcancer, stroke, diabetes, hepatomegaly, cardiovascular disease includingcardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease,autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergicdisorders including asthma, inflammation, neurological disorders andhormone-related diseases.
 25.

of Form B, C, or D.
 26.


27. 28.
 29. 30.
 31. 32.
 33. 34. 35.